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WO1999058711A1 - Procede servant a diagnostiquer ou a evaluer une predisposition a la maladie d'alzheimer - Google Patents

Procede servant a diagnostiquer ou a evaluer une predisposition a la maladie d'alzheimer Download PDF

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Publication number
WO1999058711A1
WO1999058711A1 PCT/AU1999/000362 AU9900362W WO9958711A1 WO 1999058711 A1 WO1999058711 A1 WO 1999058711A1 AU 9900362 W AU9900362 W AU 9900362W WO 9958711 A1 WO9958711 A1 WO 9958711A1
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Prior art keywords
disease
alzheimer
chromosome
gene
markers
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English (en)
Inventor
John Kwok
Peter Robert Schofield
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Garvan Institute of Medical Research
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Garvan Institute of Medical Research
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Priority to AU38032/99A priority Critical patent/AU3803299A/en
Publication of WO1999058711A1 publication Critical patent/WO1999058711A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/172—Haplotypes

Definitions

  • This invention relates to methods for diagnosing or assessing a predisposition to Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • ⁇ -A4 beta-amyloid peptide
  • NFTs neurofibrillary tangles
  • ⁇ -A4 deposits can be directly neurotoxic, in part through the generation of free radicals [5], or that ⁇ -A4 can disrupt ionic homeostasis and lead to severe effects on cellular processes and induction of neuronal cell death [5].
  • the amyloid cascade hypothesis postulates that the deposition of ⁇ -A4 is the central causative event in AD and that the NFTs, cell death and dementia follow as a direct result of this deposition [6].
  • the amyloid cascade hypothesis predicts that mutations in genes, which lead to the overproduction of APP or subsequent mismetabolism, would underlie the genetic basis of AD.
  • Familial Alzheimer's Disease is a dominantly inherited disorder that presents prior to 65 years of age and accounts for 10% of all AD cases.
  • the neuropathology of familial AD patients is indistinguishable from that of sporadic AD, the study of these familial forms of AD has led to a greater understanding of AD.
  • Linkage analysis has been an important tool in the elucidation of the genetic events involved in familial AD. Chromosome 21 - APP sene
  • PS-1 presenilin-1
  • PS-2 presenilin-2
  • AD genetic loci may act in the same amyloid cascade pathway as mentioned above.
  • clonal cell lines and transgenic mice which express mutant forms of the presenilin genes also have elevated production of the amyloidogenic form of the amyloid peptide, ⁇ -A442 [13].
  • AD Linkage analyses of late onset AD has defined a region on chromosome 19ql3.2 [14] which contains the candidate gene apolipoprotein E (Apo E) [15].
  • the Apo E gene contains as three co-dominant alleles, e2 (allele frequency of .08), e3 ⁇ .77) and e4 (.15) [16].
  • Association studies have shown that the frequency of the e4 allele (estimates ranging from .34 to .50) was significantly increased in AD patients (both familial late-onset and sporadic) [16].
  • Apo E may play an important role as a modifier gene, interacting with the APP gene or other AD genetic loci to produce the AD phenotype.
  • the e2 allele confers protection against development of late-onset AD [17].
  • the present invention provides a method of diagnosing or assessing an individual's predisposition to Alzheimer's disease (AD), especially early onset AD, comprising a step of determining the presence of a AD-linked marker(s) on chromosome 5.
  • AD Alzheimer's disease
  • the method comprises determining the presence of a AD- linked marker(s) on the short arm of chromosome 5. More preferably, the method comprises determining the presence of an AD-linked marker(s) between the chromosomal loci D5S1987 and D5S648.
  • the method may involve the determination of a single AD-linked marker but, more preferably, involves the determination of the presence of at least two AD-linked markers.
  • the AD-linked marker(s) are microsatellite marker(s). More preferably, the AD-linked marker(s) are selected from D5S416, D5S1987 and D5S648 and combinations thereof.
  • the step of determining the presence of a AD-linked marker(s) comprises PCR amplification and gel electrophoresis to determine the presence of a specific microsatellite allele for a given marker.
  • the present invention provides a method of diagnosing or assessing an individual's predisposition to AD, especially early onset AD, comprising a step of analysing allelic variation in relation to an AD susceptibility gene on chromosome 5.
  • the method of the second aspect comprises analysing allelic variation in relation to an AD susceptibility gene on the short arm of chromosome 5. More preferably, the method of the second aspect comprises analysing allelic variation between the chromosomal loci D5S1987 and D5S648.
  • the method of the first and second aspects of the invention may be used with similar methods for other AD-linked markers and, therefore, may provide a valuable clinical test.
  • the method of the first and second aspects may be used with methods involving determining the presence of the novel APP mutation, Leu 723 Pro and/or novel PS-1 mutations (i.e. M233T and R278T) and PS-2 mutation (i.e. M239V) described above.
  • the present invention may also be used to guide the cloning of the AD susceptibility gene on chromosome 5 and the identification of the allelic variation in the susceptibility gene that results in the allelic variant of the gene providing a higher relative risk to carriers. Testing directly for this allelic variation will be the preferred test. Cloning of the susceptibility gene on chromosome 5 may also allow identification of agents that block or enhance the action of this gene. Such agents are likely to be of value in the clinical treatment of AD.
  • the present invention provides an isolated polynucleotide molecule, comprising a nucleotide sequence substantially corresponding to the nucleotide sequence between the human chromosomal loci D5S1987 and D5S648 and which includes an AD susceptibility gene.
  • the AD susceptibility gene is an early onset AD susceptibility gene.
  • early onset AD we refer to AD wherein the mean age of onset is within the range of about 30 to about 50 years of age.
  • the terms "comprise”, “comprises” and “comprising” as used throughout the specification are intended to refer to the inclusion of a stated step, component or feature or group of steps, components or features with or without the inclusion of a further step, component or feature or group of steps, components or features.
  • Figure 1 provides the results of haplotype analysis of TAS-1 pedigree.
  • Figure 2(a) and (b) provides the results of a Three-Point linkage analysis of candidate chromosomal markers. Markers flanking the minimal haplotype region are indicated by vertical arrows.
  • Figure 3 diagrammatically shows the position of the chromosomal 5 ⁇ markers used in linkage analyses for the TAS-1 pedigree.
  • Figure 4 provides the results of haplotype analysis of KK pedigree. The analysis involved three individuals (III.4, III.5 and III.6), and showed that a recombination occurred between markers D5S630 and D5S1987.
  • the linkage model assumed that markers had 6 alleles of equal frequency.
  • AD genes The coding region of candidate AD genes (APP, PS-1, PS-2, ApoE) of affected members of TAS-1 pedigree had been previously screened by direct PCR-cycle sequencing, thus enabling the determination of the Apo E status of each member.
  • the candidate chromosomal regions of Iq31-lq32 (PS-2), 14q24.3 (PS-1), 19ql3.1 (Apo E) and 21q21 (APP) were screened. Four markers which span each chromosomal region were analysed.
  • MLINK Two-point analysis (MLINK) gave no support of linkage with markers flanking known genes: D1S413, D1S249, D1S425, D1S213, D3S1566, D3S1603, D3S1271, D3S1278, D14S258, D14S74, D14S68, D14S280, D17S798, D17S791, D17S787, D17S808, D19S221, D19S226, D19S220, D19S414, D21S1256, D21S1253, D21S263, D21S1252. All LOD scores were negative for each chromosomal region, with LOD scores ranging from -0.22 to -4.8 at zero recombination fraction.
  • a haplotype analysis was performed using markers on the candidate chromosomal arm. A disease haplotype spanning five markers was found in all three affected individuals (Fig 1). However, the putative disease haplotype is also found in one apparent unaffected (11.12).
  • the maximum LOD score increases to 2.33 at D5S416 (Table 4), a value which is 92% of the maximum simulated LOD score for the pedigree.
  • the multipoint LOD score increases to 2.49 between D5S630 and D5S416.
  • Multi-point max lod 2.14 between D5S630 and D5S416
  • Multi-point max lod 2.49 between D5S630 and D5S416
  • KK pedigree represents a family with heritable clinically- diagnosed early onset AD. This family does not, however, possess any detectable mutations in the known familial AD genes (APP, PS-1, PS-2, Apo E). Haplotype analysis was performed in the manner described for the TAS-1 pedigree, on three individuals of the KK pedigree. 11
  • the candidate disease haplotype spans a region of approximately 17.6 cM.
  • analysis of other pedigrees should significantly refine this region.
  • a physical contig of YAC, BAC and Pi clones will be constructed across the minimal disease haplotype region. This will facilitate the mapping of various novel and previously identified coding sequences.
  • Techniques for detecting coding sequences of genes in defined subchromosomal regions such as exon trapping and direct cDNA selection [26], will be used to detect novel coding sequences.
  • several promising candidates genes have already been mapped to novel AD region, including genes which code for ligands involved in neuronal survival and cell death.
  • Candidate genes will be screened for pathogenic mutations which are found only in the affected individuals of each pedigree [27]. Functional studies on the novel AD gene
  • biochemical and molecular studies can be employed to determine whether the effects of the pathogenic mutation follow the amyloid cascade pathway. This may be done by using biochemical analyses previously established by the present applicant For example, to determine whether the APP Leu723Pro mutation affects the production of ⁇ -A4, various forms of APP cDNAs were expressed in CHO cells. Stable transfectants carrying the normal and mutant versions of APP cDNAs were selected and APP cleavage products immunoprecipated with antibodies which specifically recognise various isoforms of ⁇ -A4 [28]. This demonstrated that the expression of the Leu723Pro mutation results in a twofold increase in production of ⁇ -A4 42 . This two-fold increase is also seen for the London or Swedish APP mutations and is comparable with other studies [8, 29], 12
  • the London APP mutation, as well as several presenilin mutations have been shown to induce apoptosis in transfected cells via G-protein pathways [30, 31].
  • the Leu723Pro mutation is also capable of inducing apoptosis in transiently transfected CHO cells as determined by the distinctive cleavage of genomic DNA into nucleosomal length (Fig 3b).
  • Fig 3b levels of apoptosis were quantified using a sandwich ELISA assay
  • the Leu723Pro mutation was able to induce levels of apoptosis comparable to the London mutation.
  • Such techniques will be used to analyse the biochemical pathways of the pathogenic mutation in the novel AD gene.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Pathology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Procédés servant à diagnostiquer ou à évaluer une prédisposition à la maladie d'Alzheimer (AD), en particulier, la maladie d'Alzheimer précoce. Ces procédés consistent à déterminer la présence d'un ou de plusieurs marqueurs présentant une liaison avec AD sur le chromosome 5 ou à analyser une variation allélique associée à un gène de susceptibilité à AD sur le chromosome 5.
PCT/AU1999/000362 1998-05-13 1999-05-13 Procede servant a diagnostiquer ou a evaluer une predisposition a la maladie d'alzheimer Ceased WO1999058711A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38032/99A AU3803299A (en) 1998-05-13 1999-05-13 Method for diagnosing or assessing a predisposition to alzheimer's disease

Applications Claiming Priority (2)

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AUPP3501A AUPP350198A0 (en) 1998-05-13 1998-05-13 Method for diagnosing or assessing a predisposition to alzheimer's disease
AUPP3501 1998-05-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007213A2 (fr) * 1995-08-16 1997-02-27 President And Fellows Of Harvard College Technique d'identification des genes provoquant la non-disjonction des chromosomes
WO1997027296A1 (fr) * 1996-01-26 1997-07-31 Hsc Research And Development Limited Partnership Acides nucleiques et proteines lies a la maladie d'alzheimer et leurs utilisations
EP0846764A2 (fr) * 1996-11-27 1998-06-10 Smithkline Beecham Plc Famille de facteurs alpha neurotrophiques des cellules gliales

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997007213A2 (fr) * 1995-08-16 1997-02-27 President And Fellows Of Harvard College Technique d'identification des genes provoquant la non-disjonction des chromosomes
WO1997027296A1 (fr) * 1996-01-26 1997-07-31 Hsc Research And Development Limited Partnership Acides nucleiques et proteines lies a la maladie d'alzheimer et leurs utilisations
EP0846764A2 (fr) * 1996-11-27 1998-06-10 Smithkline Beecham Plc Famille de facteurs alpha neurotrophiques des cellules gliales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SPILLANTINI M.G., DIVANE A, GOEDERT M., "Assignment of Human alpha-Synuclein (SNCA) and beta-Synuclein (SNCB) Genes to Chromosomes 4q21 and 5q35", GENOMICS, (1995), 27(2), pages 379-381. *
TANAHASHI H, TABIRA T., "Genome Structure and Chromosomal Mapping of the Gene for Fe65L2 Interacting with Alzheimer's beta-Amyloid Precursor Protein", BIOCHEM. BIOPHYS. RES. COMMUN., (10 May 1999), 258(2), pages 385-389. *

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