WO2014167074A1 - Methods for modulating rna alternative splicing in a subject in need thereof - Google Patents

Abstract

The present invention relates to methods for modulating RNA alternative splicing in a subject. In particular, the present invention relates to a method for modulating RNA alternative splicing in a subject in need thereof comprising administering the subject with a therapeutically amount of an inhibitor of mitochondrial complex I activity.

Description

METHODS FOR MODULATING RNA ALTERNATIVE SPLICING IN A SUBJECT

IN NEED THEREOF

FIELD OF THE INVENTION:

The present invention relates to methods for modulating RNA alternative splicing in a subject.

BACKGROUND OF THE INVENTION:

The human genome consists of 20,000 to 25,000 protein coding genes, but the repertoire of mRNA sequences and encoded proteins is far greater as a result of multiple RNA isoforms generated from each gene. RNA transcript diversity evolves from several mechanisms, but RNA alternative splicing represents a major factor driving phenotypic diversity in higher eukaryotes. Indeed splicing events are highly prevalent, estimated to occur for 95% of all multiexon genes. There are numerous modes of RNA alternative splicing observed, of which the most common is exon skipping. In this mode, a particular exon may be included in mRNAs under some conditions or in particular tissues, and omitted from the mRNA in others. The majority of splicing events alter the encoded protein, more than half causing a shift in the mRNA reading frame. Common genetic variants can afford changes in alternative splicing within a "normal" physiological range. However, abnormal variations in splicing are implicated in a large proportion of human genetic disorders result from splicing variants, since more up to 50% of diseases with genetic components involve splicing mutations. Mutations causing aberrant splicing typically result in nonfunctional protein or nonsense-mediated RNA decay, if a codon phase shift introduces premature termination signals. Abnormal splicing variants are also thought to contribute to the development of cancer; although such aberrant splicing products are, under normal conditions, usually safeguarded and eliminated by a posttranscriptional quality control mechanism. Accordingly, major physiological changes are governed by RNA alternative splicing. Large families of splice regulators have been identified that are, each, responsible for finely tuned effects on discrete sets of target proteins (Mukherjee et al.,2011 ; Ule et al, 2003). Activity of those splice regulators is highly controlled by a variety of signaling pathways that are dependent upon homeostatic conditions and cellular environment (Fagnani et al, 2007; Kalsotra et al, 2008; Tomczak et al, 2004; Ip et al, 2007; Zacharias et al, 1996 ). Consequently, the identification of drugs that are able to modulate RNA alternative splicing is highly desirable for therapeutic purposes, especially for reduce formation of disease-associated aberrant R A iso forms.

SUMMARY OF THE INVENTION:

The present invention relates to methods for modulating RNA alternative splicing in a subject. In particular, the present invention relates to a method for modulating RNA alternative splicing in a subject in need thereof comprising administering the subject with a therapeutically amount of an inhibitor of mitochondrial complex I activity. DETAILED DESCRIPTION OF THE INVENTION:

The inventors show that RNA alternative splicing system can be druggable, with therapeutic potentials, as demonstrated by the effects of the biguanide metformin on embryonic stem cells derivatives affected by myotonic dystrophy type I (Marteyn et al, 2011). The mechanism of action depends upon changes induced by the drug in the expression of a specific subset of splice regulators, downstream of the inhibition of mitochondrial complex I. Biological effects of metformin were shown compatible with usual therapeutic dosage in a clinical investigation that involved diabetic patients. As underscored by those latter results, as well as with cells derived from healthy embryos, metformin effect was not dependent of the myotonic dystrophy pathology. The drug, instead, appears altogether as a modifier of alternative splicing of a subset of genes, with new therapeutic potentials that may concern many more diseases besides those directly linked to defective alternative splicing. Metformin also reveals only one among many drugs that, affecting cell oxidation and possibly other homeostatic equilibriums, are also impacting RNA alternative splicing in ways that deserve to be explored further as a new pharmacological approach to many diseases.

Accordingly an aspect of the present invention relates to a method for modulating RNA alternative splicing in a subject in need thereof comprising administering the subject with a therapeutically amount of an inhibitor of mitochondrial complex I activity. As used herein, the term "RNA alternative splicing" has its general meaning in the art and refers to the regulated process during gene expression for which a single gene can encode multiple proteins. As will be understood by those skilled in the art, in the cell nucleus, eukaryotic genes are transcribed into pre-messenger RNA (pre-mRNA) which contains both exons and introns. To form mature mRNA, splicing occurs at specific sequences at the borders of exons and introns (splice sites) thereby removing introns and connecting exons to one another to form mR A, which is translated into protein. Consequently the proteins translated from alternatively spliced mRNAs will contain differences in their amino acid sequence and, often, in their biological functions. The production of alternatively spliced mRNAs is regulated by a system of trans-acting proteins (i.e. "splice regulators") that bind to cis-acting sites on the pre-mRNA itself. Such proteins include splicing activators that promote the usage of a particular splice site, and splicing repressors that reduce the usage of a particular site. Large families of splice regulators have been identified that are, each, responsible for finely tuned effects on discrete sets of target proteins (Mukherjee et al.,2011 ; Ule et al, 2003). Typically, splice regulators include but are not limited to SRSF1, SRSF6, SFPQ, RBM3, RBM4B, RBM5 and RBM45. According to the invention, the inhibitor of mitochondrial complex I activity provides a modulation of RNA alternative splicing by modulating the expression of the splice regulators. In particular, the inhibitor is able to down regulate the expression of RBM3.

As used herein, the term "mitochondrial complex I" has its general meaning in the art and refers to the first enzymatic complex involved in the mitochondrial respiratory chain. Mitochondrial complex I indeed accomplishes the transfer of electrons from metabolic fuels like glycolysis products and fatty acids to ubiquinone (Coenzyme Q), converting it to ubiquinol. Mitochondrial complex I is an L-shaped assembly of 45 different subunits. Fourteen of them are the 'core subunits' which are found in all complexes I, including the simpler bacterial enzymes. The remainin 31 are 'supernumerary subunits'. Some of the supernumerary subunits have had specific roles ascribed to them (e.g. SDAP is an acyl carrier protein), but most of them do not have specific known roles at present, but they may be involved in assembly, or required for structural stability. Of the fourteen core subunits, seven of are hydrophilic and encoded by the nuclear genome, and seven are highly hydrophobic and encoded by the mitochondrial genome. Table A provides a list of proteins involved in mitochondrial complex I. Typically, the "mitochondrial complex I activity" is defined by its NADH dehydrogenase activity. Said activity can be measured using any assay well-known in the art. These assays can measure the diaphorase-type activity of Complex I such as the "Complex I Enzyme Activity Microplate Assay Kit" from MitoSciences or alternatively measure the production of Reactive Oxygen Species through the use of the cell permeant reagent 2 ',7' -dichloro fluorescein diacetate (DCFDA), a fluorogenic dye that measures hydroxyl, peroxyl and other reactive oxygen species (ROS) activity within the cell (Cellular Reactive Oxygen Species Detection Assay Kit from ABCAM). Briefly, NADH dehydrogenase activity is measured using an electron acceptor. For example a biological electron acceptor can be ubiquinone, and an artificial electron acceptor can be ferricyanide (e.g. potassium ferricyanide). The assays typically comprise incubating a cell with NADH and the electron acceptor, and measuring the change in absorbance of NADH at 340 nm over time.

Accordingly, the term "inhibitor of mitochondrial complex I activity" refers to any compound (natural or not) that is able to disrupt the functionality of the complex, especially, by the ability of the compound to inhibit the NADH ferricyanide reductase activity or the NADH ubiquinone reductase activity. Typically, the inhibitor can provide directly its effect on the complex for example by interacting directly with a protein, in particular an enzyme involved in the complex activity or can provide indirectly its effect by limiting the availability of the substrates, cofactors or proteins involved in the complex. The inhibitor thus be selected from the group consisting of compounds acting as true enzymatic inhibitors (i.e. inhibitor of an enzyme activity by competing for example with the substrate or cofactor to the catalytic site of the enzyme), compounds capable of disrupting the organization of the complex (i.e. disrupting the interaction between the proteins involved in the a complex), compounds capable of limiting the availability of the substrates or cofactors , compounds capable of inhibiting the availability of a key protein involved in the complex (i.e. by inhibiting the expression of a protein of the complex). Inhibitors include any type of compounds and typically include small organic molecule, polypeptide, nucleic acid molecules, or any other biomolecule (e.g. a lipid).

In some embodiment, the inhibitor of mitochondrial complex I activity is selected from catechols, such as for example dopamine, 6-hydroxydopamine, L-DOPA and norepinephrine.

In some embodiments, the inhibitor of mitochondrial complex I activity is metformin. The term "metformin" as employed herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2: 1) fumarate salt, and the metformin (2: 1) succinate salt as disclosed in U.S. application Ser. No. 09/262,526 filed Mar. 4, 1999, the hydrobromide salt, the p-chlorophenoxy acetate or the embonate, and other known metformin salts of mono and dibasic carboxylic acids including those disclosed in U.S. Pat. No. 3,174,901, all of which salts are collectively referred to as metformin. The metformin employed herein may be the metformin hydrochloride salt, namely, that marketed as Glucophage.RTM. (trademark of Bristol-Myers Squibb Company).Metformin is the international nonproprietary name of 1,1-dimethylbiguanide (CAS Number 657-24-9). In some embodiments, the inhibitor of mitochondrial complex I activity is rotenone.

The term "rotenone" as used herein is a common name for the compound having the IUPAC name 2R,6aS, 12aS)-l,2,6,6a,12,12a-hexahydro-2-isopropenyl-8,9dimethoxychromeno [3 ,4 - b] furo (2 , 3 -h)cllromen-6 -one. Altemative names for this compound include Tubatoxin and Paraderil.

In some embodiments, the inhibitor of mitochondrial complex I activity is troglitazone. Troglitazone can be prepared by the process as described in Japanese Patent Application Kokai No. Sho 61-51189. In some embodiments, the inhibitor of mitochondrial complex I activity is selected from statins. As used herein the term "statin" refers to HMG-CoA reductase inhibitors, such as pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and rosuvastatin and their pharmaceutically acceptable salts thereof. The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which converts HMG-CoA to mevalonate. This is an early rate-limiting step in cholesterol biosynthesis.

In some embodiments, the inhibitor of mitochondrial complex I activity is resveratrol.

In some embodiment, the inhibitor of mitochondrial complex I activity is an inhibitor of expression of a protein of TABLE A.

An "inhibitor of expression" refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene. In a preferred embodiment of the invention, said inhibitor of gene expression is a siRNA, an antisense oligonucleotide or a ribozyme.

Inhibitors of gene expression for use in the present invention may be based on antisense oligonucleotide constructs. Anti-sense oligonucleotides, including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of the protein mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of the protein, and thus activity, in a cell. For example, antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding the protein can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion. Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).

Small inhibitory RNAs (siRNAs) can also function as inhibitors of gene expression for use in the present invention. Gene expression can be reduced by contacting the tumor, subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that gene expression is specifically inhibited (i.e. RNA interference or RNAi). Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. U.S. Pat. Nos. 6,573,099 and 6,506,559; and International Patent Publication Nos. WO 01/36646, WO 99/32619, and WO 01/68836).

Ribozymes can also function as inhibitors of gene expression for use in the present invention. Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. The mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleo lytic cleavage. Engineered hairpin or hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleolytic cleavage of the protein mRNA sequences are thereby useful within the scope of the present invention. Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.

Both antisense oligonucleotides and ribozymes useful as inhibitors of gene expression can be prepared by known methods. These include techniques for chemical synthesis such as, e.g., by solid phase phosphoramadite chemical synthesis. Alternatively, anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the R A molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters. Various modifications to the oligonucleotides of the invention can be introduced as a means of increasing intracellular stability and half-life. Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2'-0-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone.

Antisense oligonucleotides siRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector. In its broadest sense, a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide siRNA or ribozyme nucleic acid to the cells. Preferably, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector. In general, the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the the antisense oligonucleotide siRNA or ribozyme nucleic acid sequences. Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus. One can readily employ other vectors not named but known to the art.

Preferred viral vectors are based on non-cytopathic eukaryotic viruses in which non- essential genes have been replaced with the gene of interest. Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent proviral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo. Standard protocols for producing replication-deficient retroviruses (including the steps of incorporation of exogenous genetic material into a plasmid, transfection of a packaging cell lined with plasmid, production of recombinant retroviruses by the packaging cell line, collection of viral particles from tissue culture media, and infection of the target cells with viral particles) are provided in KRIEGLER (A Laboratory Manual," W.H. Freeman CO., New York, 1990) and in MURRY ("Methods in Molecular Biology," vol.7, Humana Press, Inc., Cliffton, N.J., 1991).

Preferred viruses for certain applications are the adeno-viruses and adeno-associated viruses, which are double-stranded DNA viruses that have already been approved for human use in gene therapy. The adeno-associated virus can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hematopoietic cells; and lack of superinfection inhibition thus allowing multiple series of transductions. Reportedly, the adeno-associated virus can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection. In addition, wild-type adeno-associated virus infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that the adeno-associated virus genomic integration is a relatively stable event. The adeno- associated virus can also function in an extrachromosomal fashion.

Other vectors include plasmid vectors. Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g., SANBROOK et al, "Molecular Cloning: A Laboratory Manual," Second Edition, Cold Spring Harbor Laboratory Press, 1989. In the last few years, plasmid vectors have been used as DNA vaccines for delivering antigen-encoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors. These plasmids, however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid. Some commonly used plasmids include pBR322, pUC18, pUC19, pRC/CMV, SV40, and pBlueScript. Other plasmids are well known to those of ordinary skill in the art. Additionally, plasmids may be custom designed using restriction enzymes and ligation reactions to remove and add specific fragments of DNA. Plasmids may be delivered by a variety of parenteral, mucosal and topical routes. For example, the DNA plasmid can be injected by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally. It may also be administered into the epidermis or a mucosal surface using a gene-gun. The plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and microencapsulation.

In some embodiment, the subject suffers from a disease characterized by the presence of abnormally spliced mRNAs. In particular, the method of the invention is particularly suitable for treating disorders involving aberrant isoforms. Typically, the method of the invention may be suitable for suppressing or limiting pathogenic RNA Transcripts.

The method of the invention is also particularly suitable for restoring a functionality of a protein. In particular, when a gene is mutated and said mutation causes the expression of an aberrant protein, or is responsible for the fact the protein is not expressed (e.g. the mutation introduces a premature stop codon resulting in nonsense-mediated RNA decay), the method of the invention may be suitable for expressing a functional isoform, It may be particularly suitable to prevent inclusion of exons bearing the mutation. By modulating RNA alternative splicing it is possible as demonstrated by the inventors to "skip" the targeted exons that will thus not be included in the mature mRNA. The mRNA thus no longer contains the information of the skipped exon(s) and the protein it encodes does not contain an amino acid sequence corresponding to the skipped exon(s). Accordingly, in the present specification, the expression "preventing splicing of one (or more) exon(s)" refers to the induction of a targeted deletion of said exon(s) in mature mRNA by a modification of splicing using the method of the invention.

TABLE B provides a list of targets and diseases that may benefit of the method of the invention for restoring functional proteins. In particular, the method of the present invention is useful for the treatment of a genetic disease (e.g. a monogenic disease) selected from the group consisting of myotonic dystrophy type I and progeria.

In a particular embodiment, when the subject suffers from myotonic dystrophy type I, the subject is administerd with an inhibitor of mitochondrial complex I activity that is not metformin.

In a particular, the method of the present invention is useful for the treatment of a angiogenic disease. An "angiogenic disease" is a disease associated with unregulated angiogenesis. Angiogenic diseases include but are not limited to primary and metastatic solid tumors, including carcinomas of breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, kidney, bladder, urothelium, female genital tract, (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal, and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma) and tumors of the brain, nerves, eyes, such as astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas, and meningiomas. Angiogenic diseases also relate to tumors arising from hematopoietic malignancies such as leukemias as well both Hodgkin's and non-Hodgkin's lymphomas. Angiogenic diseases also pertain to rheumatoid, immune and degenerative arthritis; various ocular diseases such as diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, retro lental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration (e.g. age-related macular degeneration), hypoxia, angiogenesis in the eye associated with infection or surgical intervention, and other abnormal neovascularization conditions of the eye. Angiogenic diseases further include skin diseases such as psoriasis; blood vessel diseases such as hemagiomas, and capillary proliferation within atherosclerotic plaques; Osier-Webber Syndrome; myocardial angiogenesis; plaque neovascularization; telangiectasia; hemophiliacjoints'; angiofibroma; and wound granulation. Other angiogenic diseases include diseases characterized by excessive or abnormal stimulation of endothelial cells, including but not limited to intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma, and hypertrophic scars, i.e. keloids, diseases that have angiogenesis as a pathologic consequence such as cat scratch disease (Rochele ninalia quintosa) and ulcers (Helicobacter pylori).

In particular, the method of the invention is useful for the treatment of cancer. Abnormally spliced mRNAs are indeed found in a high proportion of cancerous cells. Accordingly, the method of the invention may be performed for any type of cancers selected from the group consisting of adrenal cortical cancer, anal cancer, bile duct cancer (e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, bone cancer (e.g. osteoblastoma, osteochrondroma, hemangioma, chondromyxoid fibroma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, giant cell tumor of the bone, chordoma, lymphoma, multiple myeloma), brain and central nervous system cancer (e.g. meningioma, astocytoma, oligodendrogliomas, ependymoma, gliomas, medulloblastoma, ganglioglioma, Schwannoma, germinoma, craniopharyngioma), breast cancer (e.g. ductal carcinoma in situ, infiltrating ductal carcinoma, infiltrating, lobular carcinoma, lobular carcinoma in, situ, gynecomastia), Castleman disease (e.g. giant lymph node hyperplasia, angio follicular lymph node hyperplasia), cervical cancer, colorectal cancer, endometrial cancer (e.g. endometrial adenocarcinoma, adenocanthoma, papillary serous adnocarcinroma, clear cell), esophagus cancer, gallbladder cancer (mucinous adenocarcinoma, small cell carcinoma), gastrointestinal carcinoid tumors (e.g. choriocarcinoma, chorioadenoma destruens), Hodgkin's disease, non-Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer (e.g. renal cell cancer), laryngeal and hypopharyngeal cancer, liver cancer (e.g. hemangioma, hepatic adenoma, focal nodular hyperplasia, hepatocellular carcinoma), lung cancer (e.g. small cell lung cancer, non-small cell lung cancer), mesothelioma, plasmacytoma, nasal cavity and paranasal sinus cancer (e.g. esthesioneuroblastoma, midline granuloma), nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g. embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, skin cancer (e.g. melanoma, nonmelanoma skin cancer), stomach cancer, testicular cancer (e.g. seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer (e.g. follicular carcinoma, anaplastic carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma, thyroid lymphoma), vaginal cancer, vulvar cancer, and uterine cancer (e.g. uterine leiomyosarcoma). In particular, the method of the present invention is useful for increasing or reducing off-target adverse effects of a drug. Indeed, a drug typically binds to multiple proteins in the body involving many genes. For example, the enzymes that metabolize the drug may be affected by aberrant splicing. Thus by correcting the aberrant splicing the drug will more efficient and/or will not associated with adverse side effects.

By a "therapeutically effective amount" of the inhibitor as above described is meant a sufficient amount of the inhibitor to reach a therapeutical effect. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Preferably, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.

The Inhibitor of the invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.

"Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.

Preferably, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol ; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The Inhibitor of the invention can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifusoluble agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.

Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.

For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

The Inhibitor of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered.

In addition to the compounds of the invention formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; liposomal formulations ; time release capsules ; and any other form currently used. The present invention also relates to a method for screening a drug for modulating RNA alternative splicing in a subject comprising the steps consisting of i) testing a plurality of test substances fot their ability to inhibit the mitochondrial compex I activity in a test cell, and ii) positeveli selecting the test substances that are able to inhibit the mirochondrial complex I activity.

Inhibition of mitochondrial compex I activity may be evaluated by any method known in the art (see for example methods decribes above).

The term "test cell" refers to any cell that can be used in an in vitro assay. In particularly, the test cell is a human test cell. The test cells may include but are not limited to cells from skin, mammary, lung, intestinal epithelium, brain, heart, eye... In one embodiment the test cell is a malignant cell. In one embodiment the test cell is stem cell (mescenhymal stem cell or pluripotent stem cells such as embryonic stem cells or IPS stem cells). In one embodiment the test celle is a stem cell which harbor a monogenic mutation in a gene of interst (for example genes described in Table B).

The test substances that have been positively selected at the end of any one of the embodiments of the in vitro screening which has been described previously in the present specification may be subjected to further selection steps in view of further assaying its in vivo properties on animal model for a disease of interest or eventually in human in the context of clinical trials. Indeed the test substances that may be selected at the end of any one of the embodiments of the in vitro screening may find various applications.

In one embodiment, the screening method of the invention may further comprise the consisting of testing the tes substances selected at the end of step ii) for their ability to modulate RNA splicing in the test cell, and positively seclecting the test substances that are able to modulate the RNA splicing in the test cell.

Typically, the ability of the test substance to modulate the RNA splicing in the test cell is evaluated for a gene of interest or a plurality of genes of interest. Said genes may be for example selected from Table B. In one embodiment the test cell is a stem cell (e.g. an embryonic stem cell) which harbours a mutation that affect RNA splicing in the cell. For example, the test cell may be the test cells described in the EXAMPLE, namely VUB03 DM1 cells. Then the splicing of INSR1, SERCA1 and TNNT2 genes may be then studied as described in the EXAMPLE. In some embodiments, the test substance of may be selected from the group consisting of peptides, peptidomimetics, small organic molecules, or nucleic acids. For example the test substance according to the invention may be selected from a library of compounds previously synthetized, or a library of compounds for which the structure is determined in a database, or from a library of compounds that have been synthetized de novo. In a particular embodiment, the test substance may be selected form small organic molecules. As used herein, the term "small organic molecule" refers to a molecule of size comparable to those organic molecules generally sued in pharmaceuticals. The term excludes biological macromolecules (e.g.; proteins, nucleic acids, etc.); preferred small organic molecules range in size up to 2000da, and most preferably up to about 1000 Da.

The test substances that have been positively selected at the end of any one of the embodiments of the in vitro screening which has been described previously in the present specification may be subjected to further selection steps in view of further assaying its in vivo properties on animal model for a disease of interest or eventually in human in the context of clinical trials. For example, the test substances selected may be evaluated in an in vivo context as described in the EXAMPLE. Brief a DM1 mouse may be adminuistered with the test substances and the recovery in motor skills may be then evaluated. The test substances thar are able to improve the motor skills of the animal model in comparison with the animal not administered with the test substances or administered with a reference molecule (e.g. metformin) may be then selected.

The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

FIGURES:

Example 1: Metformin control of multiple alternative RNA splicing opens new therapeutic potentials Methods:

The wild type and mutated human embryonic stem cell lines VUB01 and VUB03 DM1 were differentiated in MPCs, transfected with Lipofectamine LTX or not with minigenes allowing the splicing of TNNT2 and CLCN1, and then exposed during 48 hours with various chemical compounds. Total RNA from treated cells was extracted and submitted after reverse transcription to PCR and QPCR analysis to study the expressions of the splicing variant of the INSR exonl l, SERCAl exon22, TNNT2 exon5, and CLCN1 exon 7A and the expression of SRSF1, SRSF6, SFPQ, RBM3, RBM5, RBM4B, RBM45. Splicing of INSR exonl 1, SERCAl exon22, TNNT2 exon5 after treatment with metformin was also analyzed in human primary myoblasts coming from DM1 patients. Implication of SRSF1, SFPQ and RBM3 in INSR exon 11 and SERCAl exon 22 splicings was investigated through their transient extinction after transfection of siRNA from Qiagen with Lipofectamine RNAiMax in MPCs VUB03 DM1 followed by RT-QPCR and RT-PCR analysis. Quantification of ROS production in treated VUB03 DM1 was performed using the ROS Detection kit from Molecular probes in 96 well plates on an Analyst GT after normalization by the cell number in wells determined on an Arrayscan after nuclei staining with dapi. Wild type and DMSXL mice²⁰ were treated intraperinoneally for one month with saline or 60 and 180 mg/kg/day of metformin. After one month motor performance was assessed by a grip test and specific force quantified²⁰. Mice were sacrified and TA dissected for foci detection by fish and analysis of transgenic DMPK expression and splicing defects analysis by RT- PCR. INSR exonl 1 splicing was analyzed by RT-QPCR in PBLs from patients affected or not with different monogenic diseases after 48 hours of treatment with 25mM metformin and ΙΟΟμΜ troglitazone or in PBLs directly collected from diabetic non DM1 patients treated with metformin or with sitagliptin.

Results and discussion: Myotonic dystrophy type I (DM1) is a monogenic disease characterized by changes in the RNA alternative splicing of a number of genes, leading to abnormal protein isoform ratios and clinical consequences^6"8. Within the framework of a research program exploring pathological mechanisms in derivatives of stem cell lines derived from embryos carrying a DM1 defective gene⁵, we explored the therapeutic potential of the anti-diabetic biguanide, metformin, because insulin resistance is a hallmark of the disease.

Mesodermal precursor cells (MPCs) derived from the affected embryonic stem cell line VUB03 DM1 and the control cell line VUB01 were exposed for 48 hours to various doses of metformin. This treatment revealed a significant post-transcriptional effect since the inclusion by alternative splicing of exon 11 of INSR increased in DM1 cells. A similar shift towards exon 11 inclusion was also observed in control MPCs. In order to determine the overall biological effect of the drug in DM1 cells, the alternative splicing of a series of genes affected by the disease was explored. Reduction of the abnormally high exclusion of exon 22 was observed in MPCs for SERCAI (ATP2A1)⁹. Since some genes were not naturally expressed in MPCs, relevant minigenes were used for hcTNT⁶ and Clcnlcxonla. Correction of the splicing defects was also observed upon treatment, with decreased inclusion of exon 5 for TNNT2 and exon 7a for Clcnl. Control experiments with the hcTNT minigene mutated in the CUGBPl response element showed that the normalizing effect of metformin did not depend on the DM1- associated splice factor, CUGBPl . This was consistent with the fact that metformin affected exon 7a of Clcnl, which is not controlled by CUGBPl ¹⁰. Similar responses to metformin were observed for the endogenous expression of INSRI, SERCAI and TNNT2 in human wild type and DM1 myoblasts.

The pathway by which metformin modulates RNA alternative splicing was explored. A quantitative PCR assay was developed to quantify the relative expression of the INSR variants +/- exonl l . A vast body of literature points to activation of AMPK¹¹, inhibition of the mTOR signaling pathway ¹², and decreased mitochondrial complex I activity¹³' ¹⁴ as major molecular targets of the drug. The first two working hypotheses were excluded because neither the specific AMPK agonist, AICAR, nor the specific mTOR inhibitor, rapamycin, elicited changes in the alternative splicing of INSR exonl 1 in spite of activation of the AMPK/mTOR pathway leading to protein synthesis inhibition as measured by eEF2 phosphorylation. The role of AMPK was also excluded because the metformin effect was not altered when the drug was applied to VUB03 DM1 MPCs while the activity of AMPK was blocked with dorsomorphin. Metformin inhibits mitochondrial complex I, as monitored by the accumulation of reactive oxygen species (ROS) in MPC VUB03 DM1 treated with 25mM Metformin. A similar result was obtained when applying 2μΜ of the specific mitochondrial complex I inhibitor rotenone¹⁵ and this treatment also revealed itself to be instrumental in inducing the inclusion of exon 11 of INSR in a dose- dependent manner. Rotenone is a potent blocker of mitochondrial respiratory chain complex I in contrast to metformin, known to only provoke partial inhibition¹⁶. Therefore, troglitazone was assayed, as it shares this limited effect with metformin while otherwise influencing very different signaling pathways¹⁶' ¹⁷. Treatment of VUB03 DM1 MPCs with troglitazone confirmed the impact of this more limited mitochondrial complex I effect on INSR alternative splicing. The same effect was observed in response to resveratrol used for its ability to inhibit complex I and III of the mitochondrial respiratory chain¹⁸. Altogether, this series of pharmacological experiments pointed to a metformin mechanism of action on alternative splicing that requires a partial inhibition of mitochondrial complex I, which is known to lead to enhanced levels of reactive oxygen and nitrogen species in the cell.

Molecular mechanisms of action of the drug on alternative splicing was explored on the basis of a recent whole genome transcriptome analysis that revealed down-regulation by metformin, but not rapamycin, of seven potential splice regulators¹⁹. Among them, RT-qPCR analysis revealed that expressions of RBM4B, RBM5, RBM45 and SRSF6 transcripts were not strongly regulated while that of RBM3, SRSF1 and SFPQ decreased with increasing concentrations of metformin. Down-regulation of these three latter genes was also obtained with rotenone, troglitazone and resveratrol. A parallel, decrease in concentration of RBM3, SRSF1 and SFPQ proteins was observed by Western blot analysis in response to metformin. Independent knock-down by RNA interference of the genes encoding these three RNA- binding proteins in VUB03 DM1 MPCs differentially impacted SERCA1 exon 22 alternative splicing. Knocking down SRSF1 induced SERCA1 exon 22 inclusion while SFPQ promoted its skipping. RBM3 had no effect. This altered equilibrium in a set of splice regulators governing the same alternative splice with opposite effects likely plays a role in the final protein isoform ratio recorded with the metformin treatment, rather than a specific effect of the drug on a single regulator. Changes observed in INSR1 splicing of exon 11 were not statistically significant, suggesting additional, yet unrevealed mechanisms.

To determine the biological effects of metformin in vivo, a DM1 mouse model having motor performance defects associated with the introduction of a mutant DMPK construct was used²⁰. DM1 mice were treated for a month with a daily dose of 60 or 180 mg/kg. Metformin induced no changes in either mutant DMPK expression or nuclear aggregates. In contrast, the treatment did impact alternative splicing, as shown by exon 5 inclusion being restored in the muscle-associated gene m-titin in the diaphragm, a gene that exhibits the greatest splicing alterations in this mouse model. In parallel, a statistically significant recovery in motor skills was observed in the grip test after treatment. This improvement was observed while the drug had no general metabolic effect on skeletal muscle, as verified by muscle weight and maximal tetanic force normalized to weight of the tibialis anterior.

We took the opportunity of patients currently being treated with metformin for type 2 diabetes mellitus, to check whether the drug affected alternative splicing at therapeutic doses in humans. In order to perform a clinical trial in which metformun would be temporarily replaced by another anti-diabetic drug, preliminary experiments were carried out in vitro on peripheral blood lymphocytes (PBLs) and sitagliptin was selected as it did not show any effect on alternative splicing of INSR1. Fifteen diabetic patients who had been on a stable dose of metformin between 2.1 and 3g/day for more than a year were then involved in a study where metformin was replaced by sitagliptin for one month (NCT 01349387). It was checked that this change in treatment induced no difference in blood glucose levels. Despite wide physiological variability in INSR expression, a statistically significant shift in the transcript ratio towards inclusion of exon 11 was observed with metformin intake. A statistically significant correlation was observed between the decreased INSR + exon 11 / - exon 11 ratio with sitagliptin intake and its increase after restarting metformin treatment.

The primary result of this study is that metformin, at doses that are compatible with clinical use, impacts the alternative splicing of many genes having abnormal isoform ratios in cells from DM1 patients. These biological data, along with the motor improvement in a mouse disease model, pave the way for a clinical trial assessing the effects of metformin in patients with DM1 not only on defects in glucose consumption but more broadly on all symptoms associated to the disease.

Potentially as important, the action of metformin on alternative splicing has been shown to not depend on a pre-existing pathology and several other drugs that discretely affect cellular oxidative equilibrium had similar impacts. Central to these biological effects is a subset of members of the vast group of splice regulators¹. The demonstration that their transcriptional levels can be modulated by drugs opens a path that may have far-reaching clinical applications. Affecting the expression of subsets of splice regulators may reveal itself to be instrumental for therapeutics applied to diseases that would benefit from exon skipping²¹. Even more broadly, altering the isoform ratio of certain proteins may be clinically relevant because the various protein iso forms have clearly differential roles. Along that line, it was interesting to note that alternative splicing of FAS exon 6, which gives rise to either a pro- or an anti-apoptotic protein²²' ²³ , was strongly affected by metformin in diabetic patients.

REFERENCES:

Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. 1. Singh, R. K. & Cooper, T. A. Pre-mRNA splicing in disease and therapeutics.

Trends Mol Med 18, 472-82.

2. Mukherjee, N. et al. Integrative regulatory mapping indicates that the RNA- binding protein HuR couples pre-mRNA processing and mRNA stability. Mol Cell 43, 327- 39.

3. Ip, J. Y. et al. Global analysis of alternative splicing during T-cell activation.

Rna 13, 563-72 (2007).

4. Zacharias, D. A. & Strehler, E. E. Change in plasma membrane Ca2(+)- ATPase splice-variant expression in response to a rise in intracellular Ca2+. Curr Biol 6, 1642-52 (1996).

5. Marteyn, A. et al. Mutant human embryonic stem cells reveal neurite and synapse formation defects in type 1 myotonic dystrophy. Cell Stem Cell 8, 434-44.

6. Philips, A. V., Timchenko, L. T. & Cooper, T. A. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737-41 (1998).

7. Charlet, B. N. et al. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10, 45-53 (2002).

8. Savkur, R. S. et al. Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet 74, 1309-13 (2004).

9. Kimura, T. et al. Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+- ATPase in myotonic dystrophy type 1. Hum Mol Genet 14, 2189-200 (2005).

10. Kino, Y. et al. MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1. Nucleic Acids Res 37, 6477-90 (2009).

11. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108, 1167-74 (2001). 12. Kalender, A. et al. Metformin, independent of AMPK, inhibits mTORCl in a rag GTPase-dependent manner. Cell Metab 11, 390-401.

13. El-Mir, M. Y. et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275, 223-8 (2000).

14. Owen, M. R., Doran, E. & Halestrap, A. P. Evidence that metformin exerts its anti- diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348 Pt 3, 607-14 (2000).

15. Zou, M. H. et al. Activation of the AMP-activated protein kinase by the antidiabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem 279, 43940-51 (2004).

16. Brunmair, B. et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53, 1052-9 (2004).

17. Nadanaciva, S., Dykens, J. A., Bernal, A., Capaldi, R. A. & Will, Y. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured

OXPHOS complex activities and respiration. Toxicol Appl Pharmacol 223, 277-87 (2007).

18. Zini, R., Morin, C, Bertelli, A., Bertelli, A. A. & Tillement, J. P. Effects of resveratrol on the rat brain respiratory chain. Drugs Exp Clin Res 25, 87-97 (1999).

19. Larsson, O. et al. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc Natl Acad Sci U S A 109, 8977-82.

20. Huguet, A. et al. Molecular, physiological, and motor performance defects in DMSXL mice carrying >1,000 CTG repeats from the human DM1 locus. PLoS Genet 8, el003043.

21. Stoilov, P., Lin, C. H., Damoiseaux, R., Nikolic, J. & Black, D. L. A high- throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators. Proc Natl Acad Sci U S A 105, 1 1218-23 (2008).

22. Cheng, J. et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263, 1759-62 (1994).

23. Moore, M. J., Wang, Q., Kennedy, C. J. & Silver, P. A. An alternative splicing network links cell-cycle control to apoptosis. Cell 142, 625-36. TABLE A: list of the proteins which are the component of the mitochondrial complex I.

Approved Approved Name Previous Synonyms Chromosome Symbol Symbols

MT-ND1 mitochondrially encoded MTND1 ND1, NAD1 mitochondria

NADH dehydrogenase 1

MT-ND2 mitochondrially encoded MTND2 ND2, NAD2 mitochondria

NADH dehydrogenase 2

MT-ND3 mitochondrially encoded MTND3 ND3, NAD3 mitochondria

NADH dehydrogenase 3

MT-ND4 mitochondrially encoded MTND4 ND4, NAD4 mitochondria

NADH dehydrogenase 4

MT-ND4L mitochondrially encoded MTND4L ND4L, NAD4L mitochondria

NADH dehydrogenase 4L

MT-ND5 mitochondrially encoded MTND5 ND5, NAD5 mitochondria

NADH dehydrogenase 5

MT-ND6 mitochondrially encoded MTND6 NAD6, ND6 mitochondria

NADH dehydrogenase 6

NDUFA1 NADH dehydrogenase MWFE, CI- Xq24

(ubiquinone) 1 alpha MWFE

subcomplex, 1, 7.5kDa

NDUFA2 NADH dehydrogenase B8 5q31.2

(ubiquinone) 1 alpha

subcomplex, 2, 8kDa

NDUFA3 NADH dehydrogenase B9 19ql3.42

(ubiquinone) 1 alpha

subcomplex, 3, 9kDa

NDUFA4 NADH dehydrogenase MLRQ, CI-9k 7p21.3

(ubiquinone) 1 alpha

subcomplex, 4, 9kDa

NDUFA5 NADH dehydrogenase B13, NUFM, CI- 7q31.33

(ubiquinone) 1 alpha 13KD-B,

subcomplex, 5, 13kDa UQOR13, CI- 13kB NDUFA6 NADH dehydrogenase B14, LYRM6, 22ql3.2 (ubiquinone) 1 alpha CI-B14,

subcomplex, 6, 14kDa NADHB14

NDUFA7 NADH dehydrogenase B14.5a 19pl3.2

(ubiquinone) 1 alpha

subcomplex, 7, 14.5kDa

NDUFA8 NADH dehydrogenase PGIV, MGC793 9q33.2

(ubiquinone) 1 alpha

subcomplex, 8, 19kDa

NDUFA9 NADH dehydrogenase NDUFS2L SDR22E1, CI- 12pl3.3

(ubiquinone) 1 alpha 39k

subcomplex, 9, 39kDa

NDUFA10 NADH dehydrogenase CI-42k 2q37.3

(ubiquinone) 1 alpha

subcomplex, 10, 42kDa

NDUFA11 NADH dehydrogenase B14.7 19pl3.3

(ubiquinone) 1 alpha

subcomplex, 11, 14.7kDa

NDUFA12 NADH dehydrogenase DAP13, B17.2 12q22

(ubiquinone) 1 alpha

subcomplex, 12

NDUFA13 NADH dehydrogenase CGI-39, 19pl3.11

(ubiquinone) 1 alpha CDA016,

subcomplex, 13 GRIM- 19,

GRIM 19, B 16.6

NDUFAB1 NADH dehydrogenase SDAP, 16pl2.3

(ubiquinone) 1 , alpha/beta FASN2A, ACP subcomplex, 1 , 8kDa

NDUFB1 NADH dehydrogenase MNLL, CI- 14q31.3

(ubiquinone) 1 beta MNLL

subcomplex, 1 , 7kDa

NDUFB2 NADH dehydrogenase AGGG, CI- 7q34

(ubiquinone) 1 beta AGGG subcomplex, 2, 8kDa

NDUFB3 NADH dehydrogenase B12 2q33.1

(ubiquinone) 1 beta

subcomplex, 3, 12kDa

NDUFB4 NADH dehydrogenase B15 3ql3.33

(ubiquinone) 1 beta

subcomplex, 4, 15kDa

NDUFB5 NADH dehydrogenase SGDH, CI- 3q27.1

(ubiquinone) 1 beta SGDH,

subcomplex, 5, 16kDa MGC12314

NDUFB6 NADH dehydrogenase B17, CI 9pl3.2

(ubiquinone) 1 beta

subcomplex, 6, 17kDa

NDUFB7 NADH dehydrogenase B18, CI-B18, 19pl3.12

(ubiquinone) 1 beta MGC2480

subcomplex, 7, 18kDa

NDUFB8 NADH dehydrogenase ASHI, CI-ASHI 10q24.31

(ubiquinone) 1 beta

subcomplex, 8, 19kDa

NDUFB9 NADH dehydrogenase B22, UQOR22, 8q24.13

(ubiquinone) 1 beta LYRM3

subcomplex, 9, 22kDa

NDUFB10 NADH dehydrogenase PDSW 16pl3.3

(ubiquinone) 1 beta

subcomplex, 10, 22kDa

NDUFB11 NADH dehydrogenase ESSS, NP17.3, Xpl l .3

(ubiquinone) 1 beta Npl5

subcomplex, 11, 17.3kDa

NDUFC1 NADH dehydrogenase KFYI 4q31.1

(ubiquinone) 1, subcomplex

unknown, 1 , 6kDa

NDUFC2 NADH dehydrogenase B14.5b, HLC-1 l lql4.1

(ubiquinone) 1, subcomplex unknown, 2, 14.5kDa

NDUFS1 NADH dehydrogenase CI-75k 2q33-q34

(ubiquinone) Fe-S protein

1, 75kDa (NADH- coenzyme Q reductase)

NDUFS2 NADH dehydrogenase CI-49 lq23.3

(ubiquinone) Fe-S protein

2, 49kDa (NADH- coenzyme Q reductase)

NDUFS3 NADH dehydrogenase CI-30 l lpl l . l l

(ubiquinone) Fe-S protein

3, 30kDa (NADH- coenzyme Q reductase)

NDUFS4 NADH dehydrogenase AQDQ, CI- 18 5ql l . l

(ubiquinone) Fe-S protein

4, 18kDa (NADH- coenzyme Q reductase)

NDUFS5 NADH dehydrogenase CI- 15k Ip34.2-p33

(ubiquinone) Fe-S protein

5, 15kDa (NADH- coenzyme Q reductase)

NDUFS6 NADH dehydrogenase CI-13kA 5pl5.33

(ubiquinone) Fe-S protein

6, 13kDa (NADH- coenzyme Q reductase)

NDUFS7 NADH dehydrogenase PSST, 19pl3

(ubiquinone) Fe-S protein FLJ46880,

7, 20kDa (NADH- FLJ45860, CI-20 coenzyme Q reductase)

NDUFS8 NADH dehydrogenase TYKY, CI-23k l lql3.2

(ubiquinone) Fe-S protein

8, 23kDa (NADH- coenzyme Q reductase) NDUFV1 NADH dehydrogenase CI-51K l lql3 (ubiquinone) flavoprotein 1,

51kDa

NDUFV2 NADH dehydrogenase CI-24k 18pl l .22

(ubiquinone) flavoprotein 2,

24kDa

NDUFV3 NADH dehydrogenase CI- 10k 21q22.3

(ubiquinone) flavoprotein 3,

lOkDa

TABLE B: Selection of monogenic pathologies for which a modulation of alternate splicing, leading to a shift in ratio of isoforms, may bear therapeutic consequences.

Gene Nb Pheno Name Category

exo

ns

ABCA1 50

HDLD familial HDL deficiency metabo lism/lipopr

(hypoalphalipoproteinemia),autosomal otein- lipid dominant, without proven predisposition

to coronary artery disease

HDLDT1 Tangier disease,autosomal metabo lism/lipopr recessive,characterized by orange tonsils otein- lipid enlarged liver,spleen,lymph

nodes,associated with very low HDL

cholesterol level

(analphalipoproteinemia) ,raised

triglycerides,peripheral neuropathy and

accumulation of cholesterol esters in

macrophages

ABCA4 50

ARMD2 age related macular dystrophy 2 eye

(heterozygous ABCA4 defect), see also

STGD1

CORD4 cone-rod dystrophy 4, characterized by eye

initial loss of visual acuity and macular

chorioretinal atrophy, followed by a

constriction of the peripheral visual field

RP19 retinitis pigmentosa 19,retinal rod-cone eye

dystrophy,autosomal recessive

characterized by initial night blindness in

the first decade,followed by a decrease of

visual acuity in the 2nd decade with distinctive features of choriocapillaris

atrophy

STGD1 Stargardt disease, juvenile, macular eye

dystrophy 1, autosomal recessive,

characterized by decreased central vision,

atrophy of the macula and underlying

retinal pigment epithelium and frequent

yellow "flavimaculatus flecks" in the

posterior pole of the retina, including late

onset fundus flavimaculatus

ABCC8 39

PHHID1 persistent hyperinsulinemia and metabo lism/ carboh hypoglycemia of infancy with pancreatic ydrates nesidioblastosis,diffuse 1

PHHIF persistent hyperinsulinemia and metabo lism/ carboh hypoglycemia of infancy with focal ydrates, adenomatous hyperplasia of islet cells of endocrinology pancreas and loss of heterozygosity of the

l ip 15.5 maternally imprinted region or

paternal mutation of SUR1 and maternal

loss of l ip 15 imprinted genes,paternally

mutated in focal adenomatous hyperplasia

with hyperinsulinism

ACSL4 16

MRX63 mental retardation, X-linked 63 mental retardation

MRX68 mental retardation, X-linked 68 mental retardation

ADAMT 20

S13 TTPF thrombotic thrombocytopenic hematology,

purpura,familial,autosomal kidney and urinary semidominant,characterized by anemia tract

and thrombocytopenia due to

intravascular destruction of erythrocytes

and blood platelets,diffuse platelet-rich

microthrombi in small vessels of mutiple

organs with the major complications

including renal failure and neurologic

dysfunction including true hemolytic and

uremic syndrome (HUS)

uss Schulman-Upshaw syndrome with hematology

congenital microangiopathic hemolytic

anemia,thrombocytopenia

AIPL1 6

CORD3 retinal cone-rod dystrophy 3 eye

LCA4 Leber congenital amaurosis type 4, eye

autosomal recessive, characterized by

congenital non evolutive blindness, with

pendular nystagmus, anterior keratoconus,

roving eye movements, absent ocular

pursuit and eye poking, severe

photophobia, hypermetropia, normal

fundus at birth followed by salt and

pepper aspect of retina and typical RP,

non recordable ERG

ALS2 34

ALS2 familial amyotrophic lateral sclerosis, neurology

juvenile type, autosomal recessive

IAHSP spastic paralysis ,infantile onset,ascending neurology

PLSJ primary lateral sclerosis juvenile neurology

ANKH 12 CCAL2 chondrocalcinosis 2 (calcium osteo-articular pyrophosphate-dihydrate deposition

disease) with early-onset

o steo arthritis, calcium pyrophosphate

dihydrate deposition disease

CMDJ craniometaphyseal osteo-articular dysplasia,characterized by

hypertelorism,hyperostosis and abnormal

modeling,increased density of tubular

bones and metaphyseal

widening,especially of the lower

limbs,dominant typejackson type

APC 15

APC adenomatous polyposis coli,also included digestive

: attenuated form (mutation codons 1595 tract/ gastrointestin to 2844),Gardner syndrome,some cases of al

Turcot syndrome,congenital hypertrophy

of retinal pigment epithelium with

mutations codons 463-1387,desmoid

tumors (mutations codons 1444-1598 and

1924) and other extracolonic

manifestations

CHRPE retinal pigment epithelium,congenital digestive

hypertrophy,Gardner syndrome including tract/ gastrointestin Turcot's syndrome (with association to al, eye malignant tumor of the CNS)

FIF fibromatosis familial digestive

infiltrative,desmoid,hereditary tract/ gastrointestin al

APOA1 4 APOAl autosomal dominant systemic amyloidosis cardiovascular, non neuropathic with widely deposition of kidney and urinary amyloid and a great clinical variation tract, digestive among and between families with major tract/liver and clinical problems related to renal,hepatic annex

or cardiac involvement (APOAl defect

with a single extrapositive charge)

CCLD corneal opacities with HDL deficiency, metabolism/lipopr including analphalipoproteinemia otein-lipid, eye (corneal clouding)

FAP3 familial amyloid polyneuropathy III,Iowa connective tissue type (ApoAl variant,deposit) including

Van Allen type

APOB 29

APOB abetalipoproteinemia,normotriglyceridemi metabo lism/lipopr c (ApoB-100 absence), Steinberg type, otein-lipid including familial hypobeta

lipoproteinemia

AHLP acanthocytosis, hypobetalipoproteinemia metabo lism/lipopr otein-lipid

HPCHB primary hypercholesterolemia with metabo lism/lipopr peripheral vascular disease, familial otein-lipid ligand defective APO-B (receptor binding

defective LDL) and/or myocardial

infarction susceptibility with an

insertion/deletion polymorphism in the

signal peptide

ATP2A2 21

AKV acrokeratosis verruciformis, Hopf disease dermatology

with warty hyperkeratotic lesions on the

dorsal aspect of the hands and feet and on

the knees and elbows , without evidence of

dyskeratosis DAR keratosis follicularis, Darier-White dermatology

disease, characterized by warty papules

and plaques in seborrheic areas,

palmoplantar pits and distinctive nail

abnormalities

ATP7A 23

MNK Menkes syndrome,X-linked recessive metabolism/mental disorder of copper metabolism, lethal in

childhoold

OHS occipital horn syndrome, allelic to MNK, connective tissue, previously known as Ehlers-Danlos metabo lism/mental syndrome type IX, characterized by skin

laxity, hyperextensible joints, bladder

diverticula, caracteristic occipital

exostoses

ATP8B1 27

BRIC benign recurrent intrahepatic digestive

cholestasis, SummerskiU syndrome , allelic tract/liver and to PFICl annex

PFIC1 progressive (fatal) familial intrahepatic digestive

cholestasis,Byler disease,characterized by tract/liver and high serum bile concentration with annex

intermittent jaundice,normal serum

gamma-glutamyl transferase and low

biliary salt concentrations,and

extrahepatic features such as pancreatitis

and marked intestinal

malabsorption,allelic to BRIC

ATRX 34

ATRX thalassemia alpha (Hb H), mental metabolism/porph retardation syndrome, with facial yrin and heme dysmorphism and epilepsy absent speech,

non deletion type, X linked, including mild or moderate mental retardation

without characteristic facial features

CHLS Chudley-Lowry syndrome, with moderate mental retardation to severe mental retardation, short stature,

mild obesity, hypogonadism, anteverted

nares, inverted -V-shaped upper-lip and

macrostomia, allelic to ATRX

CWS mental retardation X-linked syndrome, osteo-articular,

Carpenter Waziri type including coarse mental retardation facies, brachydactyly and short stature,

allelic to ATRX

JMS Juberg-Marsidi syndrome of mental congenital

retardation,with growth malformation, ear, retardation, deafness ,microgenitalism, allel mental ic to ATRX retardation, sex- genitalia

SFMS Smith-Fineman-Myers congenital

syndrome,characterized by a severe malformation, mental retardation,microcephaly,growth mental retardation failure,facial anomalies and bilateral

cryptorchidism overlapping with the

ATRX syndrome

SHS mental retardation, X-linked, syndromic, neurology, mental with spastic diplegia (Sutherland-Haan retardation syndrome) and microcephaly, lean body

habitus, short stature, striking facial

appearance with long narrow faces,

upward slant of the eyes, malar

hypoplasia, prognathism, high-arched

palate and nasal speech. In addition, small

testes and midline defects as anal atresia

or imperforate anus, clefting of palate and/or uvula, iris coloboma and Tetralogy

of Fallot

BCS1L 7

GRACIL growth metabo lism/lipopr E retardation,aminoaciduria,cholestasis,iron otein- lipid,

overload,lactic acidosis and early metabo lism/metal death,fmnish people ,Fellman syndrome

TELF complex 3 deficiency with metabo lism/lipopr tubulopathy,encephalopathy and liver otein- lipid failure

BTK 19

AGMGH agammaglobulinemia and isolated growth defense and X hormone deficiency,X- linked ,with short immunity,

stature, retarded bone age and delayed endocrinology onset of puberty and immunodeficiency

characterized by absent specific antibody

production ,Fleisher syndrome

AGMX1 agammaglobulinemia, X- linked 1, Bruton defense and type immunity

AGMX2 agammaglobulinemia,X-linked 2,with defense and isolated growth hormone deficiency, same immunity as AGMX1

CACNA 48

1A

BPTI benign paroxysmal torticollis of infancy neurology

characterized by recurrent episodes of

head tilt secondary to cervical

dystonia,often accompanied by vomiting,

pallor, and ataxia, settling spontaneously within hours or days,between land 5

years

EA2 episodic (paroxysmal) vestibular neurology cerebellar ataxia, autosomal dominant,

beginning in the first or second decade,

with long lasting dysarthria and interictal

nystagmus, atrophy of the cerebellar

vermis, acetazolamide responsive,

without myokymia, may be associated to

primary generalized epilepsy, allelic to

SCA6

MHP1 migraine, familial, hemiplegic, neurology with/without aura, associated with a

permanent cerebellar ataxia

SCA6 ataxia, spinal cerebellar 6, (autosomal neurology dominant cebellar ataxia type I)

characterized by a predominant cerebellar

phenotype without retinal degeneration,

progressive, with anticipation and triplet

CAG repeat amplification in the

intracellular C-terminus region of

CACNA1A calcium channel, allelic to

EA2, most frequently sporadic, with

numerous oval or rod shaped aggregates

in the Purkinje cells leading to their

degeneration, and atrophy of the cerebellar

vermis

CASQ2 11

VIST ventricular tadrycardio, stress-induced cardiovascular

(and catecholamine induced)

VTSIP1 ventricular tachycardia, stress-induced, cardiovascular catecholaminergic, with syncope seizures

or sudden death CASR 7

HHC1 hypercalcemia endocrinology hypocalciuric,familial,benign 1 , autosomal

dominant with neuromuscular symptoms

hyperphosphatemia and inappropriately

low levels of parathyroid

hormone,including any cases of wild

hypocalcemia with hyperphosphatemia

and normal PTH

HPT2 hypop arathyroidism, auto somal dominant endocrinology

HYPOCA mild hypocalcemia with endocrinology hyperphosphatemia and normal PTH

levels

HYPOCA hypocalcemia severe,autosomal dominant kidney and urinary B ,with Barrter-like syndrome , tract

nephrocalcinosis, impaired renal function

, clinical features of Bartter syndrome

(see 241200): decrease in distal tubular

fractional chloride reabsorption rate and

negative NaCl balance ,

hypomagnesemia, hypokalemia with

metabolic alkalosis, hyperreninemia, and

hyperaldosteronemia

NSHPT neonatal severe endocrinology hyperparathyroidism,heterozygous or

homozygous mutation of HHC1

CDH23 13

DFNB12 neurosensory recessive deafness 12,non ear

syndromic,prelingual,stable,profound

USH1D Usher syndrome type ID, characterized by ear, eye

profound congenital neurosensory

deafness, constant vestibular dysfunction

and retinitis pigmentosa of prepubertal onset, leading to blindness

CLCN1 23

MCR myotonia, generalized, Becker disease neuromuscular

MCT myotonia congenita,autosomal dominant neuromuscular

(Thomsen disease),including myotonia

levior

CLCN5 12

FILWP familial idiopathic low molecular weight kidney and urinary proteinuria,proximal tubulopathy with tract

relatively conserved renal function in

young patients,without rickets

NPHL1 nephrolithiasis,recessive,X linked, with metabo lism/memb renal failure,same gene as Dent syndrome rane transport and X-linked hypophosphatemic rickets

NPHL2 X-linked recessive hypophosphatemic metabo lism/memb rickets, proximal renal tubular syndrome rane transport with low molecular weight

proteinuria,hypercalciuria,nephrocalcinosi

s and progressive renal failure, including

Dent syndrome,(same gene as

XR /NPHLl,OMIM 300009) and the

Japan variant

CLCNK 20

B

BSNDL Bartter syndrome type IV like with kidney and urinary sensorineural deafness and salt wasting, tract, ear hypokalemic metabolic alkalosis,

autosomal recessive, with

polyhydramnios, premature birth,

postnatal polyuria and hypokalemic

hypochloremic metabolic alkalosis, and a

typical appearance, a prominent forehead, triangular facies with drooping mouth,

and large eyes and pinnae

CLCNKB Bartter syndrome,type III, characterized kidney and urinary by hypokalemic metabolic acidosis and tract

renal salt wasting,and a highly variable

phenotype ranging from episodes of

severe dehydratation in neonatal period to

almost asymptomatic patients during

adolescence

GTMS2 Gitelman syndrome 2, hypokalemic kidney and urinary alkalosis in conjunction with tract

hypocalciuria and hypomagnesemia,

hypermagnesiuria, late age of presentation

(>15 years) and normal growth

COL 11 66

Al

AOM2 Stickler syndrome 2, autosomal dominant, ear, eye, osteo- characterized by a membranous or type 1 articular vitreous phenotype associated with

congenital myopia, midline clefting, a

flattened mid-facial appearance,

neurosensory deafness and joint

hypermobility and a degenerative

arthropathy, later in life

(arthroophthalmopathy,)

MRSH Marshall syndrome characterized by ear, eye

midface hypoplasia,saddle

nose,myopia,early-onset

cataract,neurosensory deafness

progressive,predominantly cochlear

without defective morphogenesis of the

osseous labyrinthe,short stature

COL 11 66 A2

DFNA13 neurosensory dominant deafness 13,non ear

syndromic,postlingual,non progressive

and predominantly affecting middle

frequencies

OCDD osteochondrodysplasia with neurosensory connective tissue deafness, cleft palate, without eye

involvement, including dominant

Stickler-like syndrome

OSMED otospondylomegaepiphyseal dysplasia connective tissue

(chondrodystrophy with neurosensory

deafness), Nance-Insley syndrome,

including flat face, severe neurosensory

deafness, cleft palate and short limbs

without ocular involvment, including

Weissenbacher-Zweymuller syndrome

(OMIM 277610)

COL1A 51

1

EDS1C Ehlers-Danlos syndrome,type I connective tissue

,gravis,classical type,characterized by

joint hyperextensibilityjoint

hypermobility,widened atrophic scars

EDS7A1 Ehlers-Danlos syndrome, arthrochalasia connective tissue type VIIA, characterized by severe

generalized joint hypermobility, with

recurrent subluxations, congenital

bilateral hips dislocations

OI1A osteogenesis imperfecta,types I & IA with connective tissue dentinogenesis imperfecta

OI2A osteogenesis imperfecta,type connective tissue

II,congenital,lethal OI3A osteogenesis imperfecta,type connective tissue

III,severe,non lethal,dominant and

recessive

OI4A osteogenesis imperfecta,type IV connective tissue moderately severe

COL1A 52

2

EDS 11 Ehlers-Danlos syndrome 11, autosomal osteo-articular, recessive , characterized by joint dermatology hypermobility, skin hyperextensibility,

and cardiac valvular defects

EDS7A2 Ehlers-Danlos syndrome, arthrochalasia connective tissue type VIIA2, characterized by severe

generalized joint hypermobility, with

recurrent subluxations, congenital

bilateral hip dislocations

MFSV Marfan syndrome variant (R618Q connective tissue substitution in COL1A2)

OI1B osteogenesis imperfecta,types I and IA connective tissue with dentinogenesis imperfecta

OI2B osteogenesis imperfecta,type connective tissue

II,congenital,lethal

OI3B osteogenesis imperfecta,type connective tissue

III,severe,non lethal,dominant and

recessive

OI4B osteogenesis imperfecta,type connective tissue

IV,moderately severe

OPM osteoporosis,postmenopausal connective tissue, osteo-articular

COL2A 53

1

ACG2 achondrogenesis II,Langer Saldino osteo-articular type,including hypochondrogenesis,lethal

dwarfism

AOM Stickler syndrome, autosomal dominant, osteo-articular, characterized by a vitreous degeneration, ear, eye Wagner type, associated with congenital

myopia (any cases with extreme myopia

and bilateral retinal detachment), midline

clefting, a flattened mid-facial

appearance, neurosensory deafness joint

hypermobility and a degenerative

arthropathy, later in life

(arthroophthalmopathy), including variant

predominantly ocular with high risk of

retinal detachment and with a few

extraocular signs

KND Kniest spondyloepiphyseal osteo-articular dysplasia,myopia and dwarfism

NSED spondylo epiphyseal osteo-articular dysplasia,mild,Namaqualand type

OAP osteoarthrosis,precocious,autosomal osteo-articular dominant, with mild spinal

chondrodysplasia,presenting usually

young adults but also in

children,characterized by

pain,stiffness,limp and varying degrees of

limitation of passive joint

movement,affecting hips,knees,hands and

elbows

PLSDT lethal short-limbed platyspondylic osteo-articular dwarfism, Torrance type

SEDC spondyloepiphyseal dysplasia,congenital, osteo-articular autosomal dominant chondrodysplasia,

characterized by disproportionate short

stature (short trunk), abnormal epiphyses,

and flattened vertebral bodies

SEMD1 spondyloepimetaphyseal dysplasia osteo-articular congenita, Strudwick type

SPPD spondyloperipheral dysplasia with short osteo-articular ulna, platyspondyly, brachydactyly,

epihyseal dyspalsia, midface hypolpasia,

early onset grade myopia

COL3A 51

1

ACRG acrogeria,see Ehlers-Danlos connective tissue syndrome,type IV (EDS4A)

EDS3 Ehlers-Danlos syndrome,type III,with connective tissue generalized joint hypermobility,minor

hyperextensibility and softness of the skin

EDS4A Ehlers-Danlos syndrome,vascular,type connective tissue

IV,autosomal dominant, arterial- ecchymotic,characterized by fragile

thin,translucent skin,leading to premature

death, extensive bruising,characteristic

facial

appearance,arterial/intestinal/uterine

fragility or rupture

EIPV1 elastoma intrapapillare perforans connective tissue verruciformis 1 ,Miescher elastoma

FAN aneurysms,familial,rare connective tissue

COL4A 52?

3 ATS2 Alport syndrome,autosomal recessive and ear, kidney and dominant forms glomerular nephritis with urinary tract abnormalities of G basement membrane

and neurosensory deafness

FBH familial benign hematuria kidney and urinary tract

COL4A

4

ATS2 Alport syndrome,autosomal recessive and ear, kidney and dominant forms glomerular nephritis with urinary tract abnormalities of G basement membrane

and neurosensory deafness

FBH familial benign hematuria kidney and urinary tract

COL5A 66

1

EDS1A Ehlers-Danlos syndrome,gravis,classical connective tissue type,characterized by joint

hyperextensibility, widened atrophic

scarsjoint hypermobility

EDS2 Ehlers-Danlos syndrome,mitis type connective tissue

II, classical type,characterized by joint

hyperextensibility joint

hypermobility,widened atrophic

scars,velvety skin and mild propensity for

bruising

COL5A 54

2

EDS1B Ehlers-Danlos syndrome,gravis type connective tissue

I, classical type characterized by joint

hyperextensibility fragile skin with

widened atrophic scars joint,mitral valve prolapse and other symptoms and

dislocation

EDS2 Ehlers-Danlos syndrome,mitis type connective tissue

II, classical type,characterized by joint

hyperextensibility joint

hypermobility,widened atrophic

scars,velvety skin and mild propensity for

bruising

COL6A 36

1

BTHM1 limb girdle muscular dystrophy,autosomal neuromuscular dominant, early onset,benign,slowly

progressive,with early flexion

contractures,Bethlem myopathy l,with a

secundary decrease in LAMB 1 expression

UCMD3 Ullrich scleroatonic muscular dystrophy neuromuscular, with muscle weakness and multiple neurology contractures at birth or in early infancy,

autosomal recessive or dominant

COL6A 28

2

BTHM1 limb girdle muscular dystrophy,autosomal neuromuscular dominant, early onset,benign,slowly

progressive,with early flexion

contractures,Bethlem myopathy l,with a

secundary decrease in LAMB 1 expression

UCMD1 Ullrich sclerotome muscular dystrophy 1, neuromuscular autosomal recessive or dominant COL7A 118

1

EBDD epidermolysis dermatology bullosa,dystrophic,dominant,acral

form,Bart,type,with congenital localized

absence of skin affecting lower

limbs,absence/deformity of

nails,blistering of skin and mucosa,also

including EBDD pruriginosa(OMIM

604129)

EBDDN epidermolysis bullosa dermatology dystrophic,dominant,neonatal

form,transient bullous epidermolysis of

the newborn including toenail

dystrophy,isolated ,by heterozygous

carrier (OMIM 607523)

EBDDT epidermolysis dermatology bullosa,dystrophic,dominant,pretibial

with lichenoid

features,albopapuloid,Pasini

type,including recessive pretibial

dystrophic epidermalysis bullosa (OMIM

131850)

EBDR epidermolysis dermatology bullosa,dystrophic,recessive,Hallopeau- Siemens type,including cases of EB

localisata

CRB1 11 LCA8 Leber congenital amaurosis type 8, eye

autosomal recessive, characterized by

congenital non evolutive blindness, with

pendular nystagmus, anterior keratoconus,

roving eye movements, absent ocular

pursuit and eye poking, severe

photophobia, hypermetropia, normal

fundus at birth followed by salt and

pepper aspect of retina and typical RP,

non recordable ERG

RP12 retinitis pigmentosa 12, autosomal eye

recessive, early onset, with para-arteriolar

preservation of the RPE

CTNS 12

CLOJ cystinosis, late-onset juvenile or kidney and urinary adolescent nephropathic tract

CONP cystinosis, ocular nonnephropathic eye,

characterized by photophobia due to metabo lism/ amino corneal cystine crystals but absence of acids

renal disease.

CTNS cystinosis, infantile, nephropathic type, kidney and urinary autosomal recessive, characterized by tract,

onset in the first year of live, tubular metabolism/membr dysfunction (renal Fanconi syndrome) ane transport with glomerular derivation progressing

throughout the first decade of life

resulting in end stage renal failure

including ocular non nephropathic form

CYP11B 9

1

CYP11B1 adrenal hyperplasia IV,hypertensive endocrinology form, female pseudohermaphroditism, with

hypertension (11 beta-hydroxylase deficiency)

GSH hereditary hypertension with primary endocrinology, aldosteronism,sensitive to dexamethasone cardiovascular

CYP19A 11

1

CYP19 pseudohermaphroditism, female endocrinology hypergonadotropic hypogonadism with

multicystic ovaries and low urinary

estrogen excretion - also virilization of

the mother during pregnancy - estrogen

deficiency in male

GCMF gynecomastia, familial (aromatase endocrinology overexpression)

DES 9

CMD1I cardiomyopathy dilated 1 autosomal cardiovascular, dominant ,without skeletal myopathy neurology

DES desmin-related myopathy characterized neuromuscular by progressive muscle weakness

spreading to truncal neck flexor, facial,

bulbar and respiratory muscles, associated

with cardiac dilated cardiomyopathy,

conduction blocks, arrhythmias restrictive

heart failure, intestinal malabsorption and

pseudoobstruction, desmin-reactive

deposits in cardiac and skeletal muscle

cells, at the biopsy, cytoplamic inclusions

immunoreactive for desmin, and

abnormal granulofilamentous aggregatase

among the myofibrils, autosomal

dominant or sporadic

DMD 86

BMD muscular dystrophy,progressive,Becker neuromuscular type (dystrophin defect)

CMD3B cardiomyopathy,dilated,X linked cardiovascular,

(dystrophin deficiency resulting in a loss neuromuscular of alpha dystroglycan membrane binding)

not associated with muscular dystrophy

DMD muscular neuromuscular dystrophy,progressive,Duchenne type

(dystrophin,absence)

OED blindness,night,congenital,stationary eye

2, some incomplete forms,with persistence

of slight rod function (dystrophin defect)

DSP 24

ARVD8 arrhythmogenic right ventricular cardiovascular dysplasia-8

DCWHK palmoplantar hyperkeratoma cardiovascular,

(hyperkeratosis), striata 2R, autosomal connective tissue recessive, associated to woolly hair and a

dilated left ventricular cardiomyopaphy,l

eading to precocious heart failure (family

from Ecuador), Carvajal syndrome,

including skin fragility wooly -hair

syndrome (OMIM 607655 )

PPKS2 palmoplantar keratoderma connective tissue

(hyperkeratosis) striata,autosomal

dominant,characterized by a linear pattern

of skin thickening on the palms and

flexion aspect of the fingers

DSPP 6

DFNA39 deafness autosomal dominant 39,with ear

dentinogenesis imperfecta 1

DGI1 dentinogenesis imperfecta 1, type II connective tissue

(putative defect of DSPP), Shields type,

osteopontin (SPP1), bone sialoprotein (IBSP) and dentin sialophosphoprotein

DMP1 excluded, associated or not with

progressive hearing loss, including

dentinogenesis imperfecta type III (DGI3)

DYSF 55

DMAT myopathy, distal, with anterior tibial onset neuromuscular and a rapidly progressive course, high

serum CK levels and absence of vacuoles

in the muscular biopsy (heterogeneous)

LGMD2B limb girdle muscular dystrophy 2B, neuromuscular beginning in the late second decade of

life, characterized by symmetrical

progressive weakness, atrophy of the

proximal limb and trunk muscles, allelic

to MM (see symbol)

MM distal muscular dystrophy, early adult

type II, autosomal recessive (Miyoshi

myopathy), characterized by an onset in

the late adolescence or early adulthood,

early and predominant involvement of

posterior calves, marked elevation of

serum CK, dystrophic features in muscle

biopsy, a slowly progressive course in the

majority of patients, allelic to LGMD2B,

with the same mutation of dysferlin

giving alternatively cases differing by the

primary muscle involvement, i.e distal

(EDM3) or proximal (LGMD2B)

EDNRB 7

ABCD albinism,black lock,cell migration ear, dermatology, disorder of the neurocytes of the gut and digestive deafness ,autosomal recessive inheritance tract/ gastrointestin al HSCR2 Hirschsprung disease,2, autosomal congenital

recessive,sometimes associated with malformation, Waardenburg syndrome,type 4,Shah- digestive

Waardenburg syndrome,see also WS4A tract/ gastrointestin al

WS4A Waardenburg syndrome,type congenital

4A,autosomal recessive,partial malformation, albinism,deafness,without dystopia digestive canthorum,may be associated to tract/ gastrointestin Hirschsprung disease,in Shah- al, ear

Waardenburg syndrome,see also

HSCR2,including ABCD syndrome:

(OMIM 600155 ) albinism,black lock,

Hirschsprung disease and deafness

ELA2 5

ELA2 cyclic neutropenia,autosomal hematology

dominant,oscillating with 21 days

periodicity and associated with a risk of

opportunistic infection during intervals of

neutropenia

SCNP1 neutropenia congenital , autosomal hematology

dominant or sporadic, ,Kostmann disease

ELN 33

ELN cutis laxa (elastin reduced expression) connective tissue, dermatology

SVAS supravalvular aortic stenosis . Localized cardiovascular or diffuse narrowing of the ascending

aorta resulting from thickening of the

aortic media, leading to ventricular

hypertrophy, fibrillative and congestive

heart failure, affecting other major

arteries, occuring as an isolated disease

(ELN defect) or as part of the Williams syndrome, see WBS

WBS Williams Beuren syndrome, cardiovascular, neurodevelopmental disorder, 1/20 000 mental

live births . characteristic facial features : retardation, elfin facies, flat nasal bridge with multisystem anteverted nares, wide mouth with fleshy

lips, periorbital fullness, epicanthal folds,

flat malar region, small mandible and

prominent cheeks . heart abnormalities,

typically supravalvular aortic stenosis

(SAVS) and peripheral pulmonary

stenosis (PPS), hyperacusis, infantile

hypercalcemia, short stature and abnormal

gait . mental retardation . behavioral

phenotype : hypersociability, deficits in

visual-spatial and global processing,

preserved language and face processing

ENPP1 25

IIAC idiopathic infantile arterial calcification cardiovascular, with calcification occuring particularly in connective tissue, the internal elastic lamina, of muscular neuromuscular arteries and stenosis due to myointimal

proliferation, and death from myocardial

infarction usually in the first 6 months

OPLL1 ossification of the posterior longitudinal osteo-articular, ligament of spine,leading to myelopathy connective tissue among Japanase patients,locus close to

D6S276, likely located in the region

between RXRB and COLl lA2,homo log

to the ttw (tiptoe walking) in mouse

which is caused by a nonsense mutation

of Npps. In human an association of some alleles of NPPS1 and OPLLS in Japanese

population,suggests an etiologic role of

NPPS in OPLLS

EVC 23

EVC Ellis-van Creveld osteo-articular, syndrome,chondroectodermal congenital dysplasia, with short malformation, ribs,hypotrichosis,polydactyly,nails limbs, dystrophia,and dental abnormalities dermatology

WAD Weyers acrofacial dysostosis autosomal osteo-articular, dominant condition of congenital hypotelorism, dental malformation abnormalities,postaxial polydactyly,nail

dystrophy

EXT1 11

CDSM chondrosarcoma osteo-articular

EXT1 exostoses,multiple,l,also associated with osteo-articular trichorhinophalangeal syndrome in

Langer-Giedion syndrome (see LGCR)

EXT2 16

DEF11S proximal interstitial deletion of the short osteo-articular arm of chr 11, Potocki-Shaffer syndrome .

main features : skull ossification defect

(foramina parietalis permagna, FPP) and

multiple exostoses (EXT) . others: mental

retardation, facial asymetry, asymmetric

calcifications of coronary structures,

defective vision (severe myopia,

nystagmus, strabismus), skeletal

anomalies (small hands and feet, tapering

fingers), heart defects and anal stenosis

EXT2 exostoses,multiple,congenital,2,also osteo-articular, associated with foramina parietalia multisystem permagma,craniosynostosis,micropenis,m

ental retardation in a contiguous gene

syndrome with 1 lp-deletion (DEF1 IS)

EYA1 16

ASMD4 ocular anterior segment mesenchymal eye

dysgenesis 4, including Peters anomaly

and congenital cataract, autosomal

dominant

BOR branchio-oto -renal syndrome of deafness, congenital

preauricular pits, cervical fistulae, kidney malformation, eye dysplasia, including some cases without

(BO) renal involvement, excluding the

branchio-oculo-facial syndrome (BOFS),

allelic to OTFC (see also DURS1)

including Melnick-Fraser syndrome

FBN1 65

ECTL ectopia lentis, allelic to MFS1, with or connective tissue, without minor skeletal changes, eye

autosomal dominant

KPSI kyphoscoliosis, isolated, progressive, of osteo-articular variable severity

MFS1 Marfan syndrome 1, characterized by connective tissue, disproportionate tall stature with long cardiovascular, bone overgrowth (dolichostenomelia), eye

arachnodactyly, scoliosis, pectus

deformities, bilateral ectopia lentis, aortic

dilatation or dissection, . including the

severe neonatal sporadic form with

crumpled ears, flexion contractures,

pulmonary emphysema and loose skin

leading to a senile appearance and a fetal

outcome by congenital heart failure

within the first year of life . including isolated cases of thoracic aortic aneurysm

and Marfan-like syndrome (MASS,

OMIM 604308 )

SGS Shprintzen-Goldberg syndrome of congenital

marfanoid habitus craniosynostosis, malformation, arachnodactyly, abdominal hernias mental retardation

TAA thoracic aortic aneurysm cardiovascular

WMSAD Weill-Marchesani syndrome, eye, congenital characterized by short stature, malformation brachydactyly, joint stiffness and

characteristic eye abnormalities (ectopia

lentis, glaucoma, microspherophakia)

FGA 5

AFGC congenital afibrinogenemia including hematology

dysfibrogenemia alpha type,causing

bleeding diathesis or dysfibrogenemia

alpha type causing recurrent thrombosis

(OMIM 134820)

CAFG congenital afibrinogenemia, autosomal hematology

recessive, characterized by uncontrolled

bleeding after birth from umbilical cord

and high risk of spontaneous intracerebral

bleeding and splenic rupture throughout

life

FAR1 familial amyloidosis,renal,Ostertag type connective tissue

(FGA deposit)

FGFR1 15

CRS7A craniosynostosis syndromatic 7,with congenital

characteristic broad thumbs and big malformation, toes,Pfeiffer syndrome,including a case of osteo-articular Jackson- Weiss syndrome manifesting

only mild craniofacial anomalies with a Pro 252Arg mutation observed in Pfeiffer

syndrome

KAL2 Kallmann syndrome 2, hypogonadotropic endocrinology, hypogonadism and anosmia multisystem

OGD osteoglophonic dysplasia with connective, osteo- craniosynostosis, prominent supraorbital articular ridge, and depressed nasal bridge, as well

as the rhizomelic dwarfism and

nonossifying bone lesions

SCLLS atypical myeloproliferative disorder with hematology

peripheral blood eosoniphilia and stem- cell leukemia-lymphoma syndrome with a

translocation t(8; 13)(p 11 ;ql 1 - ql2),involving FGFR1 and ZNF198 or

with a translocation

t(6;8)(q27;pl l),involving FGFR1 and

FOP

FGFR2 7

ACS I acrocephalosyndactyly type 1 , Apert osteo-articular syndrome with craniosynostosis,and

syndactyly midfacial

hypoplasia,brachycephaly,ocular

proptosis,beaked nose,high arched cleft

palate,mental retardation and severe

syndactyly hands/feets

ANBXL1 Antley-Bixler syndrome 1 , osteo-articular craniosyno stosis,midface

hypoplasia,radiohumeral

synostosis,femoral bowing with neonatal

femoral fractures, fusion of carpal and

tarsal bones,Antley- Bixler-like

syndrome,autosomal dominant,associated

in any cases with genital abnormalities especially in females

CR39 craniosynostosis,syndromatic 9,with cutis dermatology

gyrata,acanthosis nigricans,digital

anomalies,urogenital abnormalities,early

death,Beare-Stevenson syndrome

CRS11 craniosynostosis, syndromic, associated osteo-articular, with ocular anterior chamber dysgenesis congenital hydrocephalus, cleverleaf skull deformity malformation, eye and elbow contractures, autosomal

dominant

CRS5A craniosynostosis, syndromatic 5, Crouzon osteo-articular, syndrome with craniofacial dysostosis congenital

malformation

CRS6 craniosynostosis,syndromatic 6,Jackson- osteo-articular,

Weiss syndrome midfacial hypoplasia and congenital hands/feet anomalies,and great malformation phenotypic variability

CRS7B craniosynostosis, syndromatic 7, with osteo-articular, characteristic broad thumbs and big toes, congenital Pfeiffer syndrome malformation

FLNA 48

BPNH bilateral periventricular nodular congenital

heterotopia in females,with epilepsy malformation, ductus arteriosus and coagulopathy,also mental retardation associated with cerebellar

hypoplasia,mental retardation,lethal in

boys

FMTD frontometaphyseal dysplasia with frontal osteo-articular hyperostosis giving great prominence to

the supraciliary ridges, underdeveloped

mandible, cryptorchidism, subluxated

radial heads, and metaphyseal dysplasia resembling that in Pyle disease

(metaphyseal dysplasia)

MLNS Melnick-Needles osteodysplasty with osteo-articular, typical facies (exophthalmos, full cheeks, connective tissue micrognathia and malalignment of teeth),

flaring of the metaphyses of long bones,

s-like curvature of bones of legs, irregular

constrictions in the ribs, and sclerosis of

base of skull

OPD1 otopalato digital syndrome,type l,with osteo-articular, deafness,cleft palate,enlarged thumbs and congenital great toes,including diaphyseal malformation incurvation

OPD2 otopalato digital type 2 with deafness, congenital

cleft palate, enlarged thumbs and great malformation toes, visceral and brain anomalies

GABRG 9

2

CAE2 chilhood absence epilepsy 2 neurology

GEFSP3 generalized epilepsy with febrile seizures neurology

plus,type 3

SMEI1 severe myoclonic epilepsy of infancy, neurology

Dravet syndrome

GCK 11

GCK familial hyperinsulinism autosomal metabo lism/ carboh dominant,characterized by hypoglycemia ydrates during fasting normal glucose tolerance

and reactive hypoglycemia after the

ingestion of glucose

MODY2 diabetes,non insulin-dependentjuvenile metabo lism/ carboh type;maturity onset diabetes of the ydrates young,2,onset in childhood mild PNDM permanent neonatal diabetes mellitus with metabo lism/ carboh complete glucokinase ydrates deficiency,autosomal recessive,in

kindreds with diverse forms of diabetes in

heterozygotes

GDAP1 6

CMT2K Charcot-Marie-Tooth disease type 2K neurology

, autosomal recessive,onset in early

childhood (younger than 3 years),

characterized by hypotonia at birth and

delayed development of early motor

milestones, in infancy difficulty walking,

foot deformities, kyphoscoliosis, distal

limb muscle weakness and atrophy,

areflexia including axonal form of CMT

with vocal cord paresis,leading to

disability by the end of the first decade

and on the sural nerve biopsy marked loss

of myelinated fibers, axonal degeneration

and regeneration, and occasional onion

bulb formations.(OMIM 607706 )

CMT4A Charcot-Marie-Tooth neuropathy type neurology

4A,demyelinating,recessive,characterized

by distal muscle weakness and

amyotrophy, sensory loss,decreased or

absent tendon reflexes,with decreased

nerve conduction

velocity,hypomyelination and basal

laminal onion bulb including axonal

neuropathy CMT2G with vocal cord

paresis ,and CMT2K

GHR 10?

GHIS1 dwarfism,Laron type,growth hormone endocrinology insensitivity syndrome 1

GHIS2 idiopathic short stature with insensitivity endocrinology to growth hormone

GJB2 2

DFNA3 neurosensory dominant deafness 3, non ear

syndromic,prelingual,slowly progressive

(GJB2 defect),(French kindred), same

locus as DFNB 1 including sudden

sensorineural hearing loss

DFNB1 neurosensory recessive deafness ear

1 ,DFNB 1 ,ηοη syndromic,prelingual,mild

to profound with a large variation among

families and a loss of hearing in the high

frequency range characteristic in children

with connexin 26 impairment,stable

associated with sloping of flat

audio metric curves and a radio logically

normal inner ear,responsible of a majority

of non syndromic deafness in a number of

populations

HID ichthyosis ,hystrix-like, with deafness ear, dermatology

KHM2 neurosensory deafness with palmoplantar dermatology keratoderma

(hyperkeratosis),mutilans,Vohwinkel

syndrome,autosomal dominant, with

ectodermal dysplasia,constricting bands

on the fifth digits of hands and feet

(pseudoainhum),including cases of

isolated neurosensory deafness and

palmar keratoderma

KID keratitis-ichthyosis-deafness syndrome ear, dermatology including keratoderma palmo-plantar

with deafness (OMIM 148350) GLB1 16

GLB1 GM1 gangliosidosis,generalized,Landing metabo lism/lysoso disease, type 3 (adult ) and type land 2 mal

(infantile and juvenile)

MPS4B mucopolysaccharidosis,type metabo lism/lysoso

IVB,Morquio disease B, severe connective mal

tissue and skeletal deformities without

neurologic involvment

GLI3 14

ACLS1 acrocallosal syndrome 1 congenital

malformation, mental retardation, neurology

GCPS Greig cephalopolysyndactyly syndrome multisystem

including preaxial and postaxial

polysyndactyly, hypertelorism

craniosynostosis and broad forehead

PAPA1 polydactyly,postaxial,type A 1, with a osteo-articular, well-formed,functional ext limbs

PHS1 Pallister-Hall syndrome 1, with congenital

hypothalamic hamartoma, central malformation Polydactyly, unperforated anus and other

malformations, including the PIV

(Polydactyly, imperforate anus and

vertebral malformation)

PPA4 Polydactyly preaxial IV osteo-articular

GNAS 12

MCAS McCune- Albright polyostotic fibrous osteo-articular, dysplasia with cafe au lait spots and endocrinology endocrine dysfunction pituitary

adenocarcinomas,including isolated bone

fibrous dysplasia,associated or not with

early cholestasis PHPIA pseudohypoparathyroidism, type IA, osteo-articular, characterized by Albright hereditary endocrinology osteodystrophy, parathyroid resistant

hypocalcemia, hyperphosphatemia and

other endocrine abnormalities, including

cases without endocrine anomalies

(pseudo-pseudohypoparathyroidism) even

in a same family, parathyroid resistance is

paternally imprinted, and PHPIA is

inherited from a female affected by either

form, maybe also due to a potential

isodisomy of chromosome 20q

POH progressive osseous heteroplasia osteo-articular, characterized by extensive dermal dermatology ossification during childhood

GUCY2 20

D

CORD6 retinal cone rod dystrophy 6, eye

characterized by initial loss of visual

acuity and abnormal color vision,

followed by night blindness and

peripheral visual field loss

LCA1 Leber congenital amaurosis type eye

1, autosomal recessive, characterized by

congenital non evolutive blindness, with

pendular nystagmus, roving eye

movements, absent ocular pursuit and eye

poking, severe photophobia and

hypermetropia , normal fundus at birth

followed by salt and pepper aspect of

retina and typical RP, non recordable

ERG

GUSB 12 GUSB hydrops fetalis metabo lism/lysoso mal

MPS7 mucopolysaccharidosis,type VII, Sly metabo lism/lysoso disease mal

HFE 7

HFE hemochromatosis, adult form, autosomal digestive

recessive, characterized by increased iron tract/liver and absorption of dietary iron leading to iron annex, metabolism accumulation and cirrhosis of the liver, metal

diabetes mellitus, skin pigmentation,

cardiac arrhythmia, failure and

arthropathy, excluding juvenile form,

with increased risk of acute myocardial

infarction in carriers of the Cys282 Tyr

mutation, but not increased risk

hepatocellular carcinoma

VGP porphyria variegata, severe phenotype metabolism metal

HPRT1 9

GHPR gout, HPRT -related, Kelley-Seegmiller metabo lism purine syndrome, HPRT1 partial deficiency or pyrimidine

HPRT1 Lesch Nyhan syndrome metabo lism purine or pyrimidine

HR 18

ALUNC alopecia universalis,characterized by dermatology

complete absence of scalp and body hair

APL atrichia with papular lesions,characterized dermatology

by early onset alopecia followed years

later by a diffuse papular

eruption,autosomal recessive

HSPG2 96

DDSH dyssegmental dysplasia, Silverman osteo-articular handmarker type,with anisospondyly and

micromelia,severe,lethal SJS1 chondrodystrophic myotonia, Schwartz- osteo-articular,

Jampel syndrome congenital

malformation, neuromuscular

IFNGR1 7

AMYF atypical defense and mycobacteriosis,familial,disseminated immunity

HPIS H. pylori infection susceptibility defense and immunity

IFNGR1 susceptibility to BCG and tuberculosis defense and mycobacterial infections (interferon immunity gamma,receptor 1 deficiency),severe

form,associated with a defect in mature

granulomas in patients with complete

deficiency,familial or sporadic

IKBKG 10

ED AID ectodermal dysplasia, anhidrotic, with defense and severe immunodeficiency and deficient immunity, natural killer cell cytotoxicity dermatology

IP2 incontinentia pigmenti 2, Bloch- dermatology, eye,

Sulzberger syndrome, familial, male- neurology lethal type, X-linked dominant, rare

neuro-cutaneous disorder involving skin,

teeth, eyes and central nervous system

characterized in females by prominent

skin signs occuring in four stages :

perinatal inflammatory vesicles,

verrucous patches of hyperpigmentation

and dermal scarring associated with

alopecia, invertis/keratitis, hypodontia,

the CNS manifestations include seizures,

spastic paralysis, microcephaly and

mental retardation, eye abnormalities lead to blindness due to retinal detachment.

Most IP females exhibit severely skewed

X-inactivation resulting from loss of cells

expressing the mutated X-chromosome

around birth. The variability in IP

phenotypes result from a combination of

the type of mutation, the functional

domain affected and X-inactivation

OLEDAI ectodermal dysplasia,anhidrotic,with defense and D lymphoedema,osteopetrosis and immunity,

immunodeficiency resulting from dermatology impaired cell responses to

liposaccharide,interleukins

IL1B,ILI8,TNF/TNFSF5 (CD40)

INSR 22

INSR diabetes mellitus,non insulin- metabo lism/ carboh dependent,insulin resistant„acanthosis ydrates nigricans,Rabson-Mendenhall syndrome,

with pineal hyperplasia and polycystic

ovarian syndrome

LPCN leprechaunism,Donohue syndrome , with metabo lism/ carboh insulin resistance ydrates

ITGB4 40

EBHF epidemo lysis bullosa of hands and dermatology

feet, Weber-Cockayne type epidermolysis

bullosa simplex

EBJPAB epidermolysis bullosa dermatology

severe,junctional,characterized by blisters

within the lamina lucida of the basement

membrane zone (BMZ),associated with

pyloric atresia,autosomal recessive

JAG1 26 ALGS Alagille syndrome, characterized by an congenital

hepatic ductular hypoplasia, with malformation, cholestasis, anomalies of vertebral digestive segmentation and valvular pulmonar tract/liver and stenosis, eye posterior embryotoxon and annex, eye retinal pigmentary changes

MCAVS multiple congenital anomalies with a congenital

defect of vertebral segmentation (butterfly malformation shaped vertebrae),likely the same as

AGS, including familial deafness

congenital heart defects and posterior

embryotoxon

TTGF tetralogy of Fallot,familial with particular cardiovascular facies

KCNQ1 16

FAF2 familial atrial fibrillation 2 cardiovascular

JLNS1 Jervell Lange-Nielsen cardioauditory cardiovascular, ear syndrome 1 of congenital neurosensory

deafness, with a long QT, syncopal

attacks and a high risk of sudden death,

autosomal recessive

LQT1 long QT syndrome with ventricular cardiovascular tachyarrhythmia,type 1, characterized by

syncopes,seizures predisposing to

torsades de pointes and ventricular

fibrillation,accounting for 50pl00 of

cases of the Romano-Ward

syndrome,potentially decreasing the

outward K+ currents,leading to a high

level of membrane

depolarization,autosomal dominant with

an autosomal recessive form associated

with compound heterozygosity for two mutations of KCNQ1

KIT 21

KIT mastocytosis with associated hematologic dermatology conditions or urticaria pigmentosa

(somatic mutations of KIT in peripheral

blood mononuclear cells)

PBT1 piebald trait l,piebaldism, with/without dermatology neurosensory deafness,homolog to

dominant spotting in mouse

K T1 9

EHK1 epidermolytic hyperkeratosis 1 dermatology

ICHM Curth-Macklin type ichthyosis hystrix dermatology with abnormality of tono fibrils and

abnormalities in supramolecular keratin

intermediate filament organization

PPK1A palmoplantar keratoderma dermatology

(hyperkeratosis),diffuse,non

epidermolytic or epidermolytic£Unna- Thost disease, including keratosis

palmoplantar striata I (OMIM 148700)

and keratosis palmoplantar striata 3

(OMIM 607654)

K T14 8

EBS2B epidermolysis bullosa,simplex,Koebner dermatology type,autosomal dominant

EBS3B epidermolysis bullosa,simplex,Weber- dermatology

Cockayne type,autosomal dominant

including epidermolysis bullosa of hands

and feet

EBS5B epidermolysis dermatology bullosa,simplex,herpetiformis,Dowling- Meara type,autosomal dominant

K T5 9

EBS2A epidermolysis bullosa,simplex,Koebner dermatology type,autosomal dominant

EBS3A epidermolysis bullosa,simplex,Weber- dermatology

Cockayne type,autosomal dominant

including epidermolysis bullosa, of hand

and feet

EBS5A epidermolysis dermatology bullosa,simplex,herpetiformis,Dowling- Meara type,autosomal dominant

EBSMP epidermolysis bullosa,simplex,with dermatology mottled pigmentation,autosomal dominant

LI CAM 27

CRASH corpus callosum agenesis, mental mental retardation retardation, adducted thumbs,spastic

paraparesis,hydrocephalus X- linked,mental retardation with clasped

thumbs,agenesis or dysgenesis of corpus

callosum

HSAS hydrocephalus 1, stenosis of the aqueduct neurology

of Sylvius;Bicker-Adams syndrome,see

CRASH

MASA MASA syndrome : mental congenital

retardation,aphasia,shuffling malformation, gait,adducted thumbs,see CRASH mental retardation

SPG1 spastic paraplegia,complicated,X- congenital

linked,see CRASH malformation, neurology

LAMA3 76?

EBJ1C epidermolysis bullosa,junctional,Herlitz dermatology type,autosomal recessive GABEB3 epidermolysis bullosa generalized dermatology

atrophic, benign 3, with dystrophy of the

nails, nonscarring blistering of skin, mild

skin atrophy, hypodontia

LOCS laryngo-onycho-cutaneous syndrome respiratory,

, autosomal recessive ,with hoarseness dermatology (which was not associated with any

obvious laryngeal lesion), dystrophic

changes in the nails, and chronic

bleeding, crusted lesions of the skin of the

face., Pakistani kindreds

LAMB3 23

EBJ1B1 epidermolysis bullosa, junctional, Herlitz dermatology

lethal type with a case resulting from

uniparental maternal isodisomy

EBJ2B epidermolysis bullosajunctional dermatology

atrophic,generalized benign,non lethal

rare form,autosomal recessive

LBR 14

HEMSK chondrodystrophy , hydropic and osteo-articular, prenatally lethal,type Moth-Eaten skeletal metabo lism/lipopr dysplasia,Greenberg syndrome otein lipid

PHA Pelger-Huet anomaly characterized by osteo-articular, hypolobulated neutrophil nuclei with hematology coarse,skeletal abnormalities

(chondrodystrophy)

LCAT 6

FED dyslipoproteinemic corneal dystrophy, eye,

Fish-Eye disease metabo lism/lipopr otein lipid

LCAT hypercho lesterolemia, unesterified, eye,

characterized by corneal opacities, target metabo lism/lipopr cell hemolytic anemia, proteinuria with otein lipid renal failure, Norum disease including

susceptibility to familial combined

hyperlipemia and premature coronary

artery disease

LMNA 12

CMD1A cardiomyopathy, dilated 1A, autosomal neuromuscular, dominant, characterized by a progressive cardiovascular disturbance in atrioventricular conduction

and a depression of cardiac contractility,

including atrial fibrrillation, early-onset

(OMIM 607554)

CMT2B1 Charcot-Marie-Tooth neuropathy type neurology

2,axonal,autosomal recessive,

characterized by an onset in the second

decade, involving upper limbs and

proximal muscles, with normal motor- nerve conduction velocity, leading to a

severe condition in less than four years

EMD2 Emery-Dreifuss muscular dystrophy 2, neuromuscular characterized by early contractures of

elbows and Achille tendons, slowly

progressive, wasting and weakness in

humeroperoneal muscles and a dilated

cardiomyopathy with life-threatening

conduction blocks. also including

asymptomatic cases, rare autosomal

recessive cases (OMIM 604929) and rares

cases associated with partial

lipodystrophy

EMD3 Emery-Dreifuss muscular dystrophy, neuromuscular autosomal recessive, characterized by

early onset contractures, a progressive course, a dilated cardiomyopathy with life

threatening conduction blocks

FPLD1 familial partial lipodystrophy autosomal metabolism/lipopr dominant ,with gradual dystrophy of otein lipid subcutaneous adipose tissue in the

extremities during puberty and

adolescence associated to insulin

resistance

,hyperinsulinemia,hypertension,dyslipide

mia,diabetes (Dunnigan-Kobberling

variety) and including any cases of SEIP

syndrome

LDHCP lipoatrophy with diabetes, hepatic connective tissue, steatosis, hypertrophic cardiomyopathy dermatology, and leukomelanodermic papules, with cardiovascular square jaw, thin lips, high forehead,

marked thinning of the eyebrows, pectus

excavatum, and narrow shoulders,

generalized atrophy of subcutaneous fat ,

concentric hypertrophy of the left

ventricle without cavity dilatation,

associated with thickened and regurgitant

valves, aortic fibrotic nodules, and

calcification of the posterior annulus

LGMD1B limb girdle muscular dystrophy IB, Dutch neuromuscular family, characterized by a slowly

progressive, proximal arm weakness,

absent ankle deep-tendon reflexes and

elevated creatine-kinase values, without

early contractures, with early onset

cardiac conduction defect MADYS1 mandibuloacral dysplasia autosomal dermatology, recessive with post-natal growth osteo-articular retardation onset at age 5, mandibular and

clavicular hypoplasia, acro-osteolysis,

delayed closure of the cranial suture, joint

contractures, mottled cutaneous

pigmentation, types A and B pattern of

lipodystrophy, marked basal and post- load hyperinsulinemia indicating insulin

resistance, partially overlapping familial

partial dystrophy of Dunnigan type (AD),

but heterozygotes in MAD clinically

asymptomatic

PROl progeria, Hutchinson-Gilford syndrome, dermatology,

autosomal dominant, characterized by osteo-articular, precocious senility and premature death, neuromuscular including post natal growth retardation,

micrognathia, absence of subcutaneous

fat, alopecia, acro-osteolysis and

premature atherosclerosis including any

atypical cases with generalized wasting,

thinned skin and survival to relatively

older age

RDMP2 restrictive dermopathy, lethal 2, tight skin congenital

contracture syndrome, autosomal malformation, recessive with severe intrauterine growth dermatology retardation, congenital contractures, and

tense skin that was easily eroded

WR 2 Werner syndrome 2, atypical , early onset connective tissue, dermatology

MAPT 15 DDPAC frontotemporal dementia (OMIM 600274) neurology,

with obsessive-compulsive behaviour and psychiatric parkinsonism with variable phenotypes disorder including hereditary Pick disease : .

pallido-ponto-nigral degeneration (OMIM

168610 ) . dysphasic disinhibition,

dystonia, muscular atrophy . amyotrophic

lateral sclerosis- parkinsonism ( OMIM

601104 ) . progressive subcortical gliosis

and pathological features comprising

neuronal loss, spongy change in multiple

areas of neocortex, presence of prions or

double PHF-tau, neurofibrillar tangles or

ubiquitin-positive inclusions

PSRP progressive supranuclear palsy, onset in neurology

the sixties, characterized by supranuclear

vertical gaze palsy, postural instability,

predominant frontal cognitive

disturbance, erect or opisthotonic posture,

spastic or ataxic dysarthria dysphagia,

with a fatal outcome with double PHF

(paired helical filaments) -tau,

neurofibrillar tangles, neuronal and glial

tau accumulation in the cortex, basal

ganglia, brainstem nuclei and white

matter

MECP2 4

MRX16 mental retardation,X- linked mental retardation

16,moderate,hyperactive deep tendon

reflexes,variable short

stature,microcephaly,in the same interval

than

MRX3 ,MRX25 ,MRX28 ,MRX41 ,MRX48 but not mutated in GDI1

MRX28 mental retardation,X- linked 28, in the mental retardation same interval than

MRX3,MRX16,MRX25 but not mutated

in GDI 1

MRX79 mental retardation X-linked,nonspecific ?

PPMX mental retardation,with manic-depressive mental retardation psychosis,pyramidal signs,parkinsonian

features and macroorchidism

RTT Rett syndrome affecting almost neurology,

exclusively the females,characterized by a psychiatric period of normal development for the first disorder

6 to 18 months followed by a progressive

deterioration leading to

dementia, autism, loss of purposeful use of

handsjerky truncal ataxia,growth

retardation and cardiac

dysfunction, including some mild forms in

females with motor coordination

problems,mild learning disability and

skewed X inactivation and in males a

congenital encephalopathy,severe mental

retardation and progressive spasticity,also

including cases presenting with the main

features of Angelman syndrome,,

including cases of non fetal,non

progressive severe encephalopathy in

males and females

MITF 8?

ADFNS albinism-deafness syndrome,autosomal ear, dermatology dominant,Tietz syndrome,characterized

by generalized hypopigmentation and congenital (prelingual) profound deafness

WS2A Waardenburg syndrome, type 2A, ear, dermatology, autosomal dominant, including partial congenital albinism, deafness without dystopia malformation canthorum, associated with ocular

albinism (TYR defect) in a case of

apparent digenism

MLH1 19

HNPCC2 non polyposis colorectal cancer digestive

2,replication error tumor (RER)+,mutator tract/ gastrointestin phenotype,including cases of Turcot al

syndrome characterized by primary brain

tumor (glioblastoma) and NPCC

MTS2 Muir-Torre syndrome (non polyposis digestive

colorectal cancer with multiple cutaneous tract/ gastrointestin sebaceous neoplasms or al

keratoacanthomas)

MPZ 6?

CMT1B Charcot-Marie-Tooth neuropathy 2 neurology

(HMSN Ib),hypertrophic

form,demyelinating,characterized by

distal muscle weakness and

amyotrophy, sensory loss,decreased or

absent tendon reflexes,with decreased

nerve conduction velocity, including

Dejerine-Sottas syndrome, neuropathy

with focally folded myelin sheathes (see

also CMT3A),and CMT2I

CMT2I axonal Charcot-Marie-Tooth disease, type neurology

2 I, with prominent sensory involvement,

very late onset, progressive, leading to

marked disability CMT2J Charcot-Marie-Tooth neuropathy, type neurology

2J,with hearing loss and pupillary

abnormalitiesfcharacterized by relatively

late onset (37 to 61 years), marked

sensory impairment, and distal muscle

atrophy and weakness

CMT3A hypomyelination neurology

neurop athy, congenital, characterized by

onset in infancy of

hypotonia,areflexia,distal muscle

weakness,very slow nerve conduction

velocity, with joint contractures or

arthrogryposis multiplex congenita

.including CMT4E

MSH2 15

HNPCC1 non polyposis colorectal cancer digestive

1 endometrial carcinoma,including Lynch tract/ gastrointestin syndrome II, replication error tumor al

(RER)+,mutator phenotype (see

MSH2),also including sporadic colorectal

carcinoma with somatic mutations of

MSH2,also including cases of Turcot

syndrome characterized by primary brain

tumor (glioblastoma) and NPCC

MTS Muir-Torre syndrome (non polyposis digestive

colorectal cancer with multiple cutaneous tract/ gastrointestin sebaceous neoplasms or al

keratoacanthomas)

MYH7 39

CMH1 cardiomyopathy,familial,hypertrophic and cardiovascular, dilated, 1, with a potential severe neuromuscular course,autosomal dominant MPD1 myopathy, autosomal dominant , distal 1 , neuromuscular infantile onset, Laing-type with slow

progression, involving proximal muscles

in the fourth decade

MY07A 49

DFNA11 neurosensory dominant deafness 11, non ear

syndromic, postlingual, progressive,

Japanese kindred, (allelic to DFNB2)

DFNB2 neurosensory recessive deafness 2,non ear

syndromic,pre or postlingual,with

variable expression,maybe associated in

some patients with a mild retinal

degeneration (atypical Usher form)

USH1B Usher syndrome, type IB, autosomal ear, eye

recessive, characterized by profound

congenital neurosensory deafness,

constant vestibular dysfunction and

retinitis pigmentosa of prepubertal onset

leading to blindness (see DFNB2)

NDP 3

COATS Coats syndrome, characterized by eye

abnormal retinal development (retinal

telangiectasia) which results in massive

subretinal lipid accumulation (exudative

retinal detachment), almost invariably

isolated, unilateral and seen in males, a

female with a variant giving birth to a son

affected with Norrie disease

EVR2 vitreoretinop athy, exudative ,rare X- linked eye

form (allelic to NDP,may be involving a

linked gene in rare cases) NDP Norrie disease (pseudoglioma), eye

characterized by congenital retinal

dysplasia, mental retardation and deafness

NDUFV 10

1

ALXD2 Alexander disease with development of neurology megalencephaly in infancy accompanied

by progressive spasticity and dementia

NDUFV 1 necrotizing encephalopathy , infantile neurology subacute of Leigh,

hypotonia, leuko dystrophy mitochondrial

with myoclonic epilepsy,complex 1

deficiency

NF1 57

NF1 neurofibromatosis 1 (von Recklinghausen neurology disease), characterized by cafe au lait

spots, axillary freckling, Lisch nodules of

the iris, multiple neurofibromas,

presumably arising from NFl inactivation

in Schwann cells, tibial pseudarthrosis

and a predisposition to certain benign and

malignant tumors of the central and

peripheral nervous system, with a variable

expression even among relatives, bearing

with the same mutation and apparently an

earlier onset or a more severe form

associated with deletions, including

neurofibrosarcoma (see TSG17C) allelic

loss, only in plexiform tumor in malignant

tumors

NFFS neurofibriomatosis,familial,spinal,without neurology cafe-au-lait macules

NFNS Noonan-neurofibromatosis syndrome cardiovascular, neurology,

dermatology

WATS cafe-au-lait spots with pulmonic stenosis neurology,

dermatology

NF2 18

NF2 neurofibromatosis 2, autosomal dominant neurology

disorder characterized by tumors of

neural-crest origin cells,with biallelic

inactivation in

schwannomas,meningiomas,mesotheliom

as,and testicular anomalies such as

presenile lens opacities,and retinal

hamartomas , (merlin/ S chwanno min

defect)

SCWT schwannomatosis,neurilemmomatosis,con neurology

genital,cutaneous

NPC1 25

NPC1 Niemann-Pick disease,type C 1 ,autosomal neurology,

recessive,a fatal neurovisceral metabo lism/lysoso disorder,characterized by ataxic mal

gait,hepato splenomegaly progression to

dementia,dysarthria,dystonia,seizures and

death at teenage, due to an error in cellular

trafficking of exogenous cholesterol with

lysosomal accumulation of unesterified

cholesterol,accounting for 95% of NPC

NPD Niemann-Pick disease,type neurology,

D,characterized by ataxic metabo lism/lysoso gait,hepatosplenomegaly,eventual mal

progression to

dementia,dysarthria,dystonia,seizures but

distinguished of type C by its less severe phenotype and by the Acadian ancestry

type,due to an error in cellular trafficking

of exogenous cholesterol with lysosomal

accumulation of unesterified cholesterol

NPHP1 4?2

0?

NPHP1 nephronophthisis, juvenile, characterized kidney and urinary by progressive insidious polyuria due to tract

reduced urinary concentrating ability

preceding the decline of renal function

and associated with an irregularly

thickened tubular basement membrane

(TBM), focal interstitial fibrosis, later

diffuse tubular-intersitial changes and

medullary cystis, leading to renal failure

and death in childhood unless treated with

dialysis or renal transplantation, including

cases associated with oculomotor apraxia

type COGAN and with cerebellar

malformations without classic symptoms

of Joubert

SLSN1 Senior-Loken syndrome 1, juvenile kidney and urinary nephronophtisis with retinal dystrophy tract, eye different from Leber congenital amaurosis

NSD1 23

STO Sotos syndrome, overgrowth syndrome . congenital

facial gestalt : long, thin face, broad malformation, forehead, fronto-temporal hair sparcity, mental retardation downslanting palpebral fissures, malar

flushing. . adults : prominence of the chin,

high hairline . macrocephaly, overgrowth

in infancy . variable learning difficulties wvss Weaver-Smith syndrome of accelerated osteo-articular, growth and osseous maturation, unusual mental retardation craniofacial appearance, hoarse and low- pitched cry, and hypertonia with

camptodactyly associated with

developmental delay

OCA2 22

AS Angelman syndrome, with a frequency of multisystem

-1/15000, resulting from defects in the

maternally imprinted domain located on

15ql lql3 . severe developmental

delay/mental retardation, profound speech

impairment, gait ataxia and/or movement

disorder, characteristic behavioural

profile including unprovoked prolonged

paroxysms of laughther and excitability .

other common features include seizures,

abnormal EEG patterns, microcephaly,

evocative facial features and

hypopigmentation . distinct phenotypes

distinguish the molecular classes of AS

OCA2 albinism, oculocutaneous 2, tyrosinase eye, dermatology positive, most common form of OCA

worldwide, especially frequent among

southern African Blacks also including a

milder hypopigmentation phenotype

known as the brown oculocutaneous

albinism (BOCA), associated to red hair

in any cases (when associated mutation of

MC1R )

PWS Prader-Willi contiguous gene syndrome, multisystem

characterized by hypotonia and feeding

difficulties in early infancy, followed in early childhood by excessive eating and

obesity, distinctive facial features,

acromicria, short stature, hypogonadism,

developmental delay, mild to moderate

mental retardation, distinctive behavioral

phenotype with temper tantrum and

obsessive compulsive mannerisms

patients with deletion have more often

seizures than patients with UPD

OTOF 48?

DFNB9 neurosensory recessive deafness 9,non ear

syndromic,prelingual,stable

NSRAN non-syndromic recessive auditory ear

neuropathy

PAF AH 11

1B1

LIS1 lissencephaly,isolated with mutation or congenital

deletion of PAF AH IB 1, including isolated malformation, subcortical laminar heterotopia neurology

MDS Miller-Dieker contiguous gene syndrome, neurology,

characterized by lissencephaly, severe to multisystem profound mental retardation and a

characteristic facial appearance and other

anomalies, including a risk of abnormal

pregnancy outcome in carriers of

balanced translocations involving the

Miller Dieker critical region

PANK2 8

HARP hypoprebetalipoproteinemia, eye, neurology, acanthocytosis, retinitis pigmentosa and metabo lism/lipopr pallidal degeneration otein lipid

PANK2 Hallervorden-Spatz disease, with eye, neurology progressive rigidity dystonia,retinitis pigmentosa, brain iron accumulation,

including forms with extensive

accumulation of both tau and alpha- synuclein . HARP syndrome

characterized by

hypoprebetalipoproteinemia,

acanthocytosis, retinitis pigmentosa, and

pallidal degeneration

PAX3 10

CDHS cranio facial-deafness-hand syndrome ear, congenital malformation

WS1 Waardenburg syndrome,type 1 , autosomal ear, eye, dominant, partial albinism and deafness, congenital with dystopia canthorum, leading to malformation failure of MITF regulation

WS3 Waardenburg syndrome type 3, ear, limbs, characterized by dystopia canthorum, congenital partial albinism and severe upper limb malformation defect (finger contractures and fusion of

carpal bones), allelic to WS 1

PAX6 14

AN aniridia, homologous to mouse small eye, eye

Drosophila eyeless, also including

atypical phenotypes such as ocular

coloboma as well as anophthalmia, foveal

hypoplasia and central nervous system

defect in compound heterozygotes

ASMD3 ocular anterior segment mesenchymal eye

dysgenesis 3, including Peters anomaly,

Axenfeld anomaly, corneal dystrophy

associated with congenital cataract,

autosomal dominant

ECTP ectopia pupillae eye FVH foveal hypoplasia,isolated eye

OPNAB optic nerve hypoplasia and aplasia, eye

bilateral, including Morning glory disc

anomaly

WAGR contiguous gene syndrome characterized eye, neoplasia, by predisposition to nephroblastoma multisystem (Wilms tumor), aniridia, genitourinary

abnormalities, mental retardation

PDE6B 22

ARRP2 retinitis pigmentosa,autosomal recessive 2 eye

(PDE6B),mouse rd homo log

CSNB3 blindness, night, congenital, stationary 3, eye

autosomal dominant

PEX7 10

PBD7 Refsum disease,phytanic acid oxidase eye, mental deficiency ,hereditary motor and sensory retardation, neuropathy 4 with ataxia, retinitis neurology pigmentosa,and polyneuropathy

complementation group 11 or R

RCDP1 rhizomelic chondrodysplasia punctata, osteo-articular, pseudo-Zellweger syndrome, caracterized metabo lism/peroxi by striking shortening of proximal limbs, somal, eye, severely disturbed endochondral bone dermatology, formation, coronal clefts of vertebrate mental retardation bodies, associated to cataract, ichthyosis,

profound growth and mental retardation

and deficiency of all four PTS2 proteins,

alkyl-dihydroxyacetone phosphate

synthase, phytanyl-CoA hydrolase, 3

ketoacyl-CoA thiolase and mevalonate

kinase participating in plasmalogen

biosynthesis, phytanic acid catabolism,

beta-oxidation of very long straight chain fatty acids and isoprenoid biosynthesis

respectively

PITX2 3

IHG2 autosomal dominant iris hypoplasia,with eye

gonio dysgenesis (iridogoniodysgenesis)

elevated intraocular pressure and

secundary glaucoma (see RIEG1)

RIEG1 ocular anterior segment mesenchymal eye

dysgenesis, Axenfeld Rieger syndrome ,

including posterior embryotoxon, iris

stromal hypoplasia and abnormalities of

pupil shape (corectopia) and number

(polycoria) and secundary glaucoma

associated with other anomalies, most

frequently anodontia/hypodontia,

maxillary hypoplasia, umbilical hernia

due a failure of involution of

periumbilical skin, see also IHG2

PKD1 46

PKD1 polycystic kidney disease 1, adult type, kidney and urinary accounting for 85% of cases, occuring by tract

a cellular recessive mechanism supporting

a two-hit model for cyst formation

(somatic mutation with LOH of PKD1 or

in (rare) cases, a somatic mutation in

PKD2 generating a heterozygous state

with mutations in both genes in the cysts),

including some severe forms with

intracranial aneurysms (5' mutation commonly associated with vascular

disease ) and/or a very early onset related

to a 2bp deletion in exon 15 of PKD1

gene

PKTS polycystic kidney disease,severe infantile kidney and urinary form of the adult type with some features tract

of tuberous sclerosis,contiguous gene

syndrome (PkDal/TSC2 locus)

PKLR 11

PKLR hemolytic anemia,non hematology

spherocytic,chronic,mild to severe

forms,autosomal recessive

PYKH high red cell ATP syndrome with hematology

pyruvate kinase hyperactivity

PLP1 7

PMDX Pelizaeus-Merzbacher disease,type 1 eye, neurology characterized by an early onset by

anormal eye

movements,progressive,mental

retardation,bilateral pyramidal signs and

evidence of white matter deficit (PLP

deficiency or overdosage)

SPG2 spastic paraplegia 2, late onset neurology

uncomplicated,X-linked

PMP22 5

CMT1A Charcot-Marie-Tooth neuropathy 1 neurology

(HMSN Ia),hypertrophic

form,demyelinating,characterized by

distal muscle weakness and

amyotrophy, sensory loss, decreased or

absent tendon reflexes,with decreased

nerve conduction velocities, (alteration of

PMP22 gene dosage is responsible of abnormal Schwann-cell growth and

differentiation),including Dejerine-Sottas

syndrome. Charcot-Marie-Tooth 1A is

associated in rare cases with deafness

(CMT1E)

HNPP neuropathy,hereditary,with liability to neurology

pressure palsies,including familial

recurrent polyneuropathy (chronic

inflammatory demyelinating

polyradiculoneurop athy, CIDP) ,tomaculou

s neuropathy, and entrappment

neuropathies such as carpal tunnel

syndrome (brachial plexus neuropathy

excluded)

RLAD Roussy-Levy hereditary areflexic dystasia ?

with early onset ,foot deformity,

weakness and atrophy of distal limb

muscles, especially the peronei, absent

tendon reflexes

PSAP 14

PSAP sphingo lipid activator proteins 1 and 2, metabo lism/lysoso combined deficiency, including mal

metachromatic leukodystrophy, atypical

Gaucher disease and complex

sphingo lipidosis with fatal infantile

storage disorder (lactosylceramide

disorder), mimicking in any cases Krabbe

disease

SAPB leukodystrophy metachromatic, variant metabo lism/lysoso with normal ARS A activity mal

SAPC Gaucher disease,variant metabo lism lysoso mal

PTEN 9 BZS Bannayan-Zonana syndrome with congenital macrocephaly,lipomas,intestinal malformation hamartomatous polyps,vascular

malformations, Hashimoto thyroiditis and

speckled penis,including Bannayan-Riley- Ruvalcaba syndrome,characterized by the

head of macro cephaly, lipomas and

pigmenta macules of the glans

penis,could be grouped with Cowden

syndrome for clinical purposes and

classified as the PTEN hamartomas-tumor

syndrome (PHTS)

JPS2 juvenile polyposis coli presenting with digestive

diarrhea,hemorrhage,protein losing tract/gastrointestin enteropathy,characterized by the al

development throughout the digestive

tract of hamartomatous polyps,including

Cowden syndrome and/or Bannayan- Riley-Pvuvalcaba syndrome

MHAM Cowden syndrome,autosomal respiratory,

dominant,characterized by multiple dermatology, hamartoma in the breast,thyroid,skin,CNS neurology and gastrointestinal tract associated with

trichilemmomas (benign tumors of the

hair follicle infundibulum) and

mucocutaneous papules which are the

hallmark of the syndrome. Including the

Lhermitte-Duclos disease with dysplastic

gangliocytoma of the

cerebellum,manifesting as

seizures,tremors and poor coordination.

Could be grouped with Bannayan- Zonana-Riley Ruvalcaba syndrome for clinical purposes and classified as the

PTEN hamartomas-tumor syndrome

(PHTS)

PROTLS Proteus-like syndrome,characterized by osteo-articular, hemihypertrophy, lower limb connective tissue asymmetry, arteriovenous malformation

and lipomatosis,not similar to Proteus

syndrome

PTHR1 14

BLOD Blomstrand chondrodysplasia,lethal osteo-articular dwarfism,with advanced endochondral

bone formation and increased bone

density

CDMJ chondrodysplasia,metaphyseal,Jansen osteo-articular type,with cranial densification,autosomal

dominant short-limbed dwarfism , with

constitutive activity of PTHR1 in Jansen's

form with hypercalcemia

RDS 3

MDBS1 macular dystrophy, autosomal dominant, eye

butterfly shaped pigmentary macular

dystrophy 1, including Zermatt macular

dystrophy, retinitis pigmentosa with

bull's- eye maculopathy and other pattern

dystrophies

RP7 retinitis pigmentosa 7, including retinitis eye

punctata albescens

RECQL 20

4

RAPADIL RAPADILINO syndrome, including osteo-articular, INO Radial defect, Patellar defect, cleft Palate, congenital

Diarrhea, Dislocated joints and Limb malformation deformation, long Nose and Normal

intelligence, poikiloderma and

Osteosarcoma likely associated,

autosomal recessive, more severely

expressed in female

RTS Rothmund Thomson syndrome, dermatology, characterized by skin atrophy and osteo-articular, eye telangiectasia with hyper and hypo

pigmentation, congenital skeletal

abnormalities, short stature, juvenile

cataract, premature ageing, increased risk

of mesenchymal tumors linked to

abnormal chromatid cohesion and

chromosomal instability

RET 20

CCHS1 congenital central hypoventilation neurology

syndrome,Ondine curse,associated with

Hirschsprung disease,Haddad

syndrome,(RET defect)

HSCR1 Hirschsprung disease 1, autosomal congenital

dominant form, characterized by intestinal malformation, blockage due to a lack of intrinsic digestive ganglion cells in the myenteric and tract/ gastrointestin submucosal plexuses of the distal al

gastrointestinal tract and an increased risk

of tumors,with variable expression and

reduced penetrance even in multiplex

kindreds,including total colonic

aganglionosis with small bowel

involvement

MEN2A endocrine neoplasia,multiple,type IIA, endocrinology

Sipple disease MEN2B endocrine neoplasia,multiple,type endocrinology

IIB,allelic to MEN2A

MTC1 thyroid carcinoma,medullary endocrinology

1 ,mutiple, with/without

pheochromocytoma (RET defect),same

gene as MEN2A;see also MEN2BJST1

RHCE 10

RH Rhesus blood group,as determined by hematology

RH-D and RH C/c-E/e (RH-CE)

loci, including hemolytic disease of the

newborn (Rhd phenotype)

RHECT blood group red-cell phenotype Rh-Evans hematology, eye

(D..), associated with cataract

RHNA blood group RH-null syndrome,amorph hematology type

RHO 5

ARRP 1 retinitis pigmentosa 1, autosomal eye

recessive 1

CSNB6 blindness, night, congenital, stationary eye

6, autosomal dominant

RP4 retinitis pigmentosa 4, autosomal eye

dominant, type I and others, including

some retinitis punctata albescens, the first

most common ADRP locus (20-31%)

RLBP1 9

ARRP7 retinitis pigmentosa, autosomal recessive eye

8, early onset, with optic disc atrophy and

macular degeneration

NFRCD news foundland rod-cone dystrophy, early eye

onset retinal dystrophy,severe,with

precoce blindness

R ALB retinitis punctata albescens,characterized eye

by congenital stationary night blindness and abnormally slow regeneration of visual pigments with uniform white- yellow dots scattered through retina,autosomal recessive,including Bothnia dystrophy (high prevalence in Northern Sweden)

RPE65 14

LCA2 Leber congenital amaurosis type 2, eye autosomal recessive, characterized by congenital blindness with pendular nystagmus, roving eye movements, absent ocular pursuit and eye poking, night blindness, normal fundus at birth followed by salt and pepper aspect of retina and typical aspect of RP, non recordable ERG, presenting a transient improvement during evolution

RP20 variable expression retinal eye dystrophy,childhood-onset,autosomal recessive 8, affecting rod and cone photoreceptors

RPGR 19

CORDX1 cone-rod dystrophy, 1 (RP2 and RP3 eye excluded), progressive retinal degeneration,characterized by progressive photophobia, decreased central vision and dyschromatopsia

MDXA1 X-linked recessive atrophic macular eye degeneration

RP15 retinitis pigmentosa 15, X-linked eye dominant,characterized by initial loss of visual acuity and color vision followed by night blindness and peripheral visual field

loss (see OMIM 300029)

RP3 retinitis pigmentosa 3, X- linked recessive eye

form of choroidoretinal degeneration

which is distinguished from other types

by the presence in heterozygous women

of a tapetal-like retinal reflex, including

retinitis pigmentosa with recurrent

respiratory infections

RPS6K 22

A3

CLS Coffm-Lowry syndrome characterized by congenital

mental retardation, short stature,evolutive malformation, coarse facies,everted lips,progressive mental retardation kyphoscoliosis,soft hands with tapering

fingers,a large variety of mutations

mostly responsible of loss of function

MRX19 mental retardation,X- linked 19 mental retardation

RUNX1 8

AML1 acute myeloid leukemia (AML-M2),or hematology

Philadelphia positive chronic

myelogenous leukemia in the blastic

phase,with breakpoint in translocation

t(8;21)(q22;q22) (see

CBFA2Tl,dysregulated by interaction

with MEF : myeloid ELF1 like factor)

and t(16;21)(q24;q22) (see CBFB),

myelodysplasia syndrome with breakpoint

in translocation t(3;21)(q26;q22) (see

EAP,EVI 1 ,MDS 1 ),acute lymphoblastic

leukemia with translocation

t(12;21)(pl3;q22),most common in

childhood leukemia (see ETV6),with low BCL2 expression and with inversions

(between D21S65-D21S55-D21S215) in

Down syndrome

FPDAML platelet autosomal dominant disorder with hematology prolonged bleeding time

thrombocytopenia, aggregation defect and

propensity to develop acute myeloid

leukemia

RYR1 106

CCO central core disease of muscle,or neuromuscular nemaline rod myopathy,characterized by

hypotonia and proximal muscle weakness

in infancy, leading to the delay of motor

milestones,with a variable severity of

symptoms,a low progressive

course,associated skeletal defects and

microscopically amorphous-looking areas

(cores) in the predominant type I

fibers;also presenting as a severe form of

multi-minicore myopathy with

ophtalmoplegia associated with presence

of rods in the muscle fibers and to

malignant hyperthermia susceptibility

MHS1 hyperthermia susceptibility, malignant 1 neuromuscular

(ryanodine receptor defect) including

abnormal electrically evoked muscle

contraction syndrome in absence of drugs

SCN1A 26

GEFS2 generalized epilepsy with febrile seizures neurology plus,2

SMEI2 severe myoclonic epilepsy in infancy 2, a neurology severe form of generalized epilepsy with febrile seizures

SCN5A 28

LQT3 long QT syndrome with ventricular cardiovascular tachyarrhythmia, type 3, characterized by

syncopes, seizures, predisposing to

torsades de pointes and ventricular

fibrillation, potentially increasing the

inward Na+ currents leading to a high

level of membrane depolarization, also

sudden infant death syndrome (frequency

unknown)

PCCD1 progressive cardiac conduction deficit, cardiovascular characterized by progressive alteration of

cardiac conduction through the His- Purkinje system with right or left bundle

branch block and large QRS complexes,

leading to complete atrioventricular block

and causing syncope and sudden death,

Lenegre-Lev disease (OMIM 113900),

including the sudden unexplained

nocturnal death syndrome (SUNDS) and

Sick sinus syndrome congenital

PCCD2 idiopathic ventricular fibrillation, with ?

sudden death, including form with a right

bundle-branch block, and long QT,

Brugada syndrome (OMIM 601144)

SCNN1 13

B

PHA1A1 pseudohypoaldosteronism,type 1 endocrinology

(SCNN1B or SCNN1G defect),autosomal

recessive,unresponsive to aldosterone

PSALD pseudoaldosteronism, hereditary endocrinology, hypertension, salt sensitive, with cardiovascular hypokalemic alkalosis, Liddle syndrome

(SCNNIB or SCNNIG defect),

autosomal dominant

SCNN1 12

G

PHA1A1 pseudohypoaldosteronism,type 1 endocrinology

(SCNNIB or SCNNIG defect),autosomal

recessive,unresponsive to aldosterone

PSALD pseudoaldosteronism, hereditary endocrinology, hypertension, salt sensitive, with cardiovascular hypokalemic alkalosis, Liddle syndrome

(SCNNIB or SCNNIG defect),

autosomal dominant

SFTPC 6

FILD familial interstitial lung disease respiratory presenting as chronic pneumonitis in

infancy, autosomal dominant

IPAP1 infantile pulmonary alveolar proteinosis respiratory

1 ,with or without fibrosing lung disease

SHOX 7

DCS dyschondrosteosis,dominant form of osteo-articular mesomelic dysplasia in pseudoautosomal

region characterized by short stature (2

SD below normal) with short forelimbs

and distal radioulnar deformity on

forearm x rays (Madelung

deformity),Leri- Weill syndrome,maybe

associated with chondrodysplasia

punctata ichthyosis and mental retardation

in a putative contiguous gene

syndrome,and in any cases isolated

Madelung deformity GCX growth control region,pseudoautosomal,X

linked,involved in some idiopatic short

stature,linear growth deficiency ,maybe

also involved in short and dysmorphic

skeletal features in Turner syndrome

(interaction with oestrogen is responsible

of premature fusion of growth plate

because of hap lo insufficiency of SHOX)

MMDL mesomelic dwarfism,recessive form,of osteo-articular the hypoplastic ulna,fibula and mandible

type,Langer type

SLC26A 2

2

ACG1B achondrogenesis IB, Fraccaro type, lethal osteo-articular dwarfism

ATSG2 atelosteogenesis, type II, lethal dwarfism, osteo-articular de la Chapelle dysplasia, including Mc

Alister dysplasia

DTD diastrophic dysplasia osteo-articular

EDM4 multiple epiphyseal dysplasia 4, with osteo-articular normal stature, hip dysplasia, double

layered patella, including cases of

apparently isolated club foot

SLC26A 21

4

DFNB4 neurosensory recessive deafness 4,non ear

syndromic,associated with temporal

abnormalities that range from isolated

enlarged vestibular acqueduct to

developmental abnormalities of cochlea

(Mondini dysplasia),prelingual,stable,Middle

Eastern Druze population

PDS neurosensory deafness, with temporal ear, endocrinology bone abnormalities that range from

isolated enlarged vestibular acqueduct

(EVA) to developmental abnormalities of

cochlea (Mondini dysplasia) and goiter,

with iodine organification defect in the

thyroid gland, Pendred syndrome, allelic

to DFNB4

SLC37A 8

4

GSD1B glycogen storage disease type IB, Von metabo lism/lipopr

Gierke disease, characterized by otein lipid hepatomegaly and hypoglycemia, lactic

acidemia, hyperuricemia, hyperlipidemia,

associated with neutropenia and

functional deficiencies of neutrophiles

and monocytes resulting in recurrent

infections

GSD1C glycogen storage disease type IC, von metabo lism/lipopr

Gierke disease, characterized by otein lipid hepatomegaly, hypoglycemia, lactic

acidemia, hyperuricemia, hyperlipidemia

not associated with neutropenia and

functional deficiencies of neutrophiles

and monocytes, maybe allelic to GSD1B

but controversial evidence

SLC4A1 20

BGW blood group- Waldner type hematology

DI Diego blood group hematology DRTAA renal tubular acidosis,distal,autosomal kidney and urinary dominant,characterized by an inadequate tract

urinary secretion resulting in alkaline pH

in presence of metabolic

acidosis, associated with hypokalemia

hypercalciuria and when untreated

nephrocalcinosis and usually mild

metabolic bone disease and normal red

cells,in relation with disorder of epithelial

polarity

EL5 elliptocytosis (ovalocytosis),Malaysian- hematology

Melanesian type

SPH5 spherocytosis,type V,uncommon hematology

SOX9 3

CMPD1 Campomelic dysplasia characterized by osteo-articular, congenital bowing and angulation of long sex-genitalia bones, together with other skeletal and

extraskeletal defects . genital defects or

sex reversal are observed in two-thirds of

XY patients . acampomelic dysplasia is

observed in some patients . a skeletal

dysplasia with Pierre-Robin sequence

may represent a mild form of campomelic

dysplasia

SRA1 sex reversal,of SOX9,autosomal in XY sex-genitalia

patients with haplo insufficiency or in XX

patients with a duplication of

SOX9,allelic to CMPDl

SPTA1 52

EL2 elliptocytosis,common,type 2 hematology HPP pyropoikilocytosis hematology

SPH3 spherocytosis,type III hematology

TAZ 11

CMD3A cardiomyopathy,dilated,lethal in cardiovascular, infancy, allelic to Barth syndrome;see neuromuscular EFE2,recessive X-linked

EFE2 dilated cardiomyopathy associated with cardiovascular, skeletal myopathy,neutropenia and connective tissue abnormal mitochondria (Barth

syndrome),including isolated

endomyocardial fibroelastosis 2 and 3- methylglutaconic aciduria

INVM isolated noncomp action of the left cardiovascular ventricular myocardium without features

of Barth syndrome but allelic to it

TCF1 10

IDDM16 diabetes mellitus,insulin-dependent metabo lism/ carboh susceptibility 16 ydrates

MODY3 diabetes non insulin dependent, juvenile metabo lism/ carboh type, maturity onset diabetes of the ydrates young3, excluding NIDDM late onset,

post puberal onset, severe form with

lower renal threshold for glucose and

frequent degenerative complications

TECTA 23

DFNA12 neurosensory dominant deafness 12,non ear

syndromic,prelingual,stable in most

patients,with mild frequency hearing

loss, allelic to DFNA8 may be acting in a

digenic mode of inheritance with

DFNA2,leading to a severe phenotype or

progressive deafness with late onset DFNA8 neurosensory dominant deafness 8,non ear

syndromic,prelingual,stable,allelic to

DFNA12

DFNB21 neurosensory recessive deafness 21,non ear

syndromic prelingual,severe to profound

TMPRS 13

S3

DFNB10 neurosensory recessive deafness ΙΟ,ηοη ear

syndromic,prelingual,stable,congenital,all

elic to DFNB8

DFNB8 neurosensory recessive deafness 8,non- ear

syndromic,postlingual,profound,progressi

ve, allelic to DFNB 10

TP73L 15

ADULT aero -dermato -ungual- lacrimal-tooth congenital

syndrome with ectrodactyly,hypoplastic malformation breasts and nipples primary hypodontia

AEC nkyloblepharon-ectodermal dysplasia- dermatology, eye clefting syndrome,Hay- Wells syndrome

LMS limb mammary syndrome,EEC-like,in a congenital

Dutch family, characterized by mammary malformation hypoplasia,ectrodactyly,lacrimal-duct- atresia,nail dysplasia,

hypohydrosis,hypodontia and cleft

palate,maybe allelic to EEC3 but no

mutations so far detected in TP63

RHS ectodermal dysplasia,anhydrotic with dermatology cleft lip,and cleft palate ,Rapp- Hodgkin

syndrome,autosomal dominant

SHFM4 ectodactyly,ectodermal dysplasia and congenital

cleft-lip/palate syndrome 3, including malformation cases of split hand/foot malformation

(OMIM 605289 ) TRPS1 7

TRPS1 trichorhinophalangeal syndrome osteo-articular,

^characterized by sparse scalp hair,a congenital bulbous tip of the nose,a long flat malformation, philtrum,a thin upper vermilion border dermatology and protruding ears,associated with

skeletal anomalies including cone-shaped

epiphyses at the phalanges,hip

malformation and short stature

TRPS3 trichorhinophalangeal syndrome 3 with osteo-articular short stature and remarkably short hands

without exostoses,mostly allelic to

TRPSl,Sugio-Kajii syndrome

TSC1 21?

FCDBC focal cortical dysplasia of Taylor balloon neurology cell type , epilepsy-associated without

additional features of neurocutaneous

phacomatosis

TSC1 tuberous sclerosis 1 , characterized by the neurology development of hamartomas in cerebral

cortex, responsible of seizures, mental

retardation and mental disorder including

autism, cortical tuber, hamartomas in

other organs, including subependymal

nodules, facial angiofibromas, subungual

fibromas, forehead plaques, shagreen

patches, cardiac rhabdomyomas and renal

angiomyo lo lipomas

TSHR 12?

GHTF gestational endocrinology hyperthyroidism,familial,autosomal

dominant,caused by a mutant of thyrotropin receptor hypersensitive to

human chorionic gonadotropin

HFTA hyperfunctioning thyroid adenoma with endocrinology somatic mutations of

TSHR,hyperthyroidism,non

immune,autosomal dominant or sporadic

congenital form

TSHR hypothyroidism,congenital,with high endocrinology

TSH,TSH unresponsiveness (TSHR

defect in few cases),including thyroid

hypoplasia

TULP1 14

LCA10 Leber congenital amaurosis type eye

10,autosomal recessive, with

nystagmus, night blindness ,profound

visual deficiency,without

hypermetropia,rod cone dystrophy

RP 14 retinitis pigmentosa,autosomal recessive eye

4,severe,early onset,characterized by

nystagmus,diminished visual acuity color

vision disturbances,bull's eye

maculopathy and peripheral pigmentary

retinopathy,associated with an

unrecordable ERG

USH1C 28

DFNB18 neurosensory recessive deafness 18,non ear

syndromic,Indian kindred,located in the

USH1C region

USH1C Usher syndrome, type IC, characterized ear, eye

by profound congenital neurosensory

deafness, constant vestibular dysfunction

and retinitis pigmentosa of prepubertal

onset, leading to blindness (British kindred -Louisiana Acadian)

USH2A 21

ARRP15 retinitis pigmentosa autosomal recessive eye

15,non syndromic

USH2A Usher syndrome, type IIA, autosomal ear, eye

recessive, congenital, moderate to severe

neurosensory deafness, progressive with

age,normal vestibular function and

retinitis pigmentosa, exhibiting

phenotypic variation, including atypical

cases with vestibular dysfunction,

including cases of non syndromic retinitis

pigmentosa

WAS 12

THC thrombocytopenia,X-linked (same gene as hematology

WASP)

WASP Wiskott-Aldrich syndrome,including hematology

isolated thrombocytopenia,with increased

apoptosis of lymphocytes

XLN severe congenital neutropenia,X- linked defense and recessive characterized by recurrent major immunity bacterial infections,associated

monocytopenia and at bone marrow

examination,arrest at the

promyelocyte/myelocyte stage

WFS1 8

DFNA14 neurosensory dominant deafness,non ear

syndromic,bilateral and symetrical,only

affecting low and mild frequencies up to

2000 Hz

DFNA38 neurosensory dominant deafness 38, ear

nonsyndromic , progressive, autosomal dominant

DFNA6 neurosensory dominant deafness 6, non ear

syndromic, postlingual, progressive, low

frequency hearing loss

WFS1 Wolfram syndrome,autosomal metabo lism/ carboh recessive,progressive neurodegenerative ydrates, ear, eye, disorder, diabetes insipidus, non kidney and urinary autoimmune insulin dependent diabetes tract mellitus,(optic atrophy,neurosensory

deafness,renal-tract abnormalities, late

ataxia and myoclonus),peripheral

neuropathy psychiatric illness, Dueto- vasopressin neuron loss in the supraoptic

nucleus and defect in precursor

processing

DDS Denys Drash syndrome, characterized by congenital

urogenital malformation, malformation, ear, pseudohermaphroditism, Wilms tumor, neurology, kidney nephroblastoma, infantile nephropathy and urinary tract with diffuse mesangial sclerosis evolving

towards a renal failure and abnormal

expression of PAX2, maybe involved in

the pathological mechanisms leading to

glomerular dysfunction ; see also GUD,

dystomia-deafness syndrome with

progressive deafness, severe dysarthria,

bizarre posturing of head and neck and

hyperactivity

FS Frasier syndrome, male kidney and urinary pseudohermaphroditism with normal tract, sex-genitalia female external genitalia, streak gonads,

with focal segmental glomerulosclerosis, nephrotic syndrome and gonadoblastoma

but no Wilms tumor, related to but

distinct from Denys-Drash syndrome

GUD genitourinary dysplasia component of congenital

WAGR (including partial androgen malformation, resistance), overlapping Denys Drash kidney and urinary syndrome (see DDS), associated with tract germline WT1 mutation

IDMS nephrotic syndrome with an isolated kidney and urinary diffuse or,rarely,a focal segmental tract mesangial sclerosis

WAGR contiguous gene syndrome characterized eye, neoplasia, by predisposition to nephroblastoma multisystem (Wilms tumor), aniridia, genitourinary

abnormalities, mental retardation

WT1 Wilms tumor susceptibility l,also kidney and urinary involved in translocation tract t(l l;22)(pl3;ql2) (see DSRCT),and in

liver tumor suppression (see TSG11G)

MCLDP McLeod phenotype (acanthocytosis, elevated C ,and neurological hematology

defects), chorea,myopathy,areflexia,neuroacanthosis

XK ell blood group precursor hematology

Claims

CLAIMS:

1. A method for modulating R A alternative splicing in a subject in need thereof comprising administering the subject with a therapeutically amount of an inhibitor of mitochondrial complex I activity.

2. The method according to claim 1 wherein the subject suffers from a disease selected from the group consisting of the diseases depicted in Table B, angiogenic diseases or and cancers.

3. The method according to claim 1 or 2 wherein the inhibitor of mitochondrial complex I activity is selected from the group consisting of catechols, metformin, statins, rotenone, troglitazone, resveratrol and inhibitors of expression of a protein selected in Table A, providing that when the subject suffers from myotonic dystrophy type I the inhibitor of mitochondrial complex I activity is not metformin.