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WO2001095855A2 - Pregnancy-associated plasma protein-e (papp-e) - Google Patents

Pregnancy-associated plasma protein-e (papp-e) Download PDF

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Publication number
WO2001095855A2
WO2001095855A2 PCT/EP2001/006831 EP0106831W WO0195855A2 WO 2001095855 A2 WO2001095855 A2 WO 2001095855A2 EP 0106831 W EP0106831 W EP 0106831W WO 0195855 A2 WO0195855 A2 WO 0195855A2
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amino acid
acid sequence
dna sequence
dna
sequence
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German (de)
French (fr)
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Harald Tschesche
Martin Farr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4715—Pregnancy proteins, e.g. placenta proteins, alpha-feto-protein, pregnancy specific beta glycoprotein
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • PAPP-E Pregnancy-associated Plasma-Protein-E
  • the invention relates to the Pregnancy-associated Plasma-Protein-E (PAPP-E).
  • PAPP-A, -B, -C and -D Pregnancy-associated Plasma Proteins
  • PAPP-C and -D were the pregnancy-specific ⁇ ⁇ glycoprotein or the placental lactogen [Lin 1974, Bohn 1971]
  • PAPP-A and -B were new proteins.
  • PAPP-B which acts as a 1300 kDa octamer from presumably identical, 74 kDa subunits.
  • P ⁇ PP-A is a monomer and forms an approximately 800 kDa disulfide-bridged 2: 2 complex with the strongly glycosylated proform of eosinophil
  • the PAPP-A / proMBP complex is also detectable in women who are not pregnant, namely in low concentrations in the granulosa cells, the folic fluid of the ovaries, in the oviduct mucosa, the cervical mucosa and the endometrium [Sinosich 1984, Sjöberg 1984 and 1986]. Low concentrations have also been measured in men, namely in testis and seminal plasma [Klopper 1985].
  • PAPP-A can be used as a diagnostic marker for fetal trisomy 21 (Down syndrome) in the maternal serum of the first trimester of pregnancy.
  • the PAPP-A / proMBP concentration measured between the sixth and fourteenth week of pregnancy, is reduced by 50 to 77 percent [Pandya 1995].
  • ßhCG free ß subunit of human chorionic gonadotropin
  • the ultrasound measurement of the fetal nuchal translucency and the age of the pregnant woman 76 to 87% of pregnancies with trisomy 21 can be recognized non-invasively in the first trimester [ including De Graaf 1999].
  • PAPP-A Triso ien 13, 18 and 22 [Bersinger 1994, Wheeler 1996, Biagotti 1998].
  • the PAPP-A gene was located on chromosome 9 and the complete cDNA sequence was cloned [Silahtaroglu 1993, Kristensen 1994].
  • the 1547 amino acid PAPP-A consists of a larger propeptide and comprises 82 cysteine residues, which are all bridged, as well as 14 potential N-glycosylation sites and 7 possible sites for glycosaminoglycan groups [Kristensen 1994].
  • PAPP-A has no overall homology to other proteins, there are five C-terminal motifs, each comprising about 60 residues, which are similar in complement-regulating proteins and selectins [Kristensen 1987 and 1994, Reid 1989].
  • the PAPP-A sequence contains three motifs of about 30 residues in length, which are related to the Lin-notch motifs in homeotic proteins of early tissue differentiation in C. elegans, D. Melanogaster and X. laevis [Kristensen 1994].
  • PAPP-A has a potential zinc binding motif with a potential Met-Turn, as occurs in the astacins, serralysins, adamalysines including some ADAMs and matrix metalloproteinases [Stöcker 1995, Bode 1996]. It has recently been shown that there is proteolytic activity against insulin-like growth factor binding protein-4 (IGFBP-4) [Lawrence 1999]. This would intervene in the so-called "IGF axis" in a regulatory manner.
  • IGFBP-4 insulin-like growth factor binding protein-4
  • IGF-I and - II insulin-like growth factors
  • IGFBP-1 to -6 insulin-like growth factor binding proteins
  • IGFBP-cleaving proteinases IGF receptors (especially IGF-IR) [Bayes-Genis 1999].
  • the IGFs from the complexes with their binding pro stones are released. This can be done by the serine proteinases plasmin and thrombin [Angelloz-Nicoud 1996, Zheng 1998], the matrix metalloproteinases MMP-1, -2 and -3 (collagenase 1, gelatinase A and stromelysin 1) [Fowlkes 1994], and by PAPP- A happen [Lawrence 1999] by cleaving the binding proteins.
  • the free IGFs can then bind to their receptors, in particular the IGF-IR, which initiates various intracellular signaling pathways as receptor tyrosine kinase. These ultimately lead to the pleiotropic effects of the IGF axis such as proliferation, differentiation and protection against apoptosis [Butt 1999], but also to pathobiochemical processes, for example in heart diseases or cancer [Ren 1999, Yu 1999].
  • the invention now relates to a cDNA sequence which encodes the human pregnancy-associated plasma protein E (PAPP-E).
  • PAPP-E human pregnancy-associated plasma protein E
  • the DNA sequence according to the invention comprises a DNA sequence which is selected from
  • allelic variations and mutations that stitution by Sub, insertion or deletion of single or several nucleotides ⁇ ren or inversion of single or multiple Nucleotidteilsequenzen the DNA sequences of (a) to (c) ER give, the variations and mutants encoding isofunctional expression products.
  • the invention further relates to an amino acid sequence comprising an amino acid sequence which is selected from
  • the invention further encompasses polyclonal or monoclonal antibodies against the above amino acid sequences and the use of the above DNA and / or amino acid sequences and / or the above antibodies in an assay for human genetic diagnostics, in particular for determining trisomy 13, 18, 21 or 22, and the use of the above DNA and / or amino acid sequences to find antagonists against PAPP-E.
  • RNA array hybridization showed that PAPP-E is expressed very specifically in placental tissue [Fig. 4]. This was demonstrated by biotinylation of the cloned PAPP-E cDNA fragment (North2South Biotin Random Prime Kit, Pierce), hybridization of the MTE-Array-2 (Pierce) and detection with the North2South-Chemiluminescent-Hybridization-and-Detection- Kit (Pierce), CL-XPosure-X-ray film (Pierce) and eukobrom developer and Superfix fixative (Tetenal).
  • the invention thus discloses or comprises the human pregnancy-associated plasma protein E (PAPP-E), the associated cDNA, DNA and RNA, and the chromosomal localization on the chromosome lq23-25, the display of the protein and derived peptides from cell cultures through the use of recombination techniques and isolation from human sera, the use of DNA and the protein and respective fragments as well as peptide and nucleic acid antagonists for therapeutic purposes, diagnostic assays for the detection of the protein and the DNA, and naturally occurring mutations.
  • PAPP-E human pregnancy-associated plasma protein E
  • the associated cDNA DNA and RNA
  • chromosomal localization on the chromosome lq23-25 the display of the protein and derived peptides from cell cultures through the use of recombination techniques and isolation from human sera, the use of DNA and the protein and respective fragments as well as peptide and nucleic acid antagonists for therapeutic purposes, diagnostic assays for the detection of the protein and the DNA, and naturally occurring mutations
  • PAPP-B Pregnancy-associated plasma protein B
  • IGF insulin-like growth factor
  • Insulin-like growth factor I as a cardiac hormone: physiological and pathological i plications in heart disease. J Mol Cardiol 31, 2049-61.
  • Hyperstimulated human preovulatory follicular fluid, luteinized cells of unruptured follicles, and corpus luteum contain pregnancy-associated plasma protein A (PAPP-A). Fertil Steril 41, 551-7. Sjöberg, J., Wahlström, T., and Seppälä, M. (1984). Preg ⁇ nancy-associated plasma protein A in the human endometrium is dependent on the effect of progesterone. J Clin Endocrinol Metab 58, 359-62.
  • Serum PAPP-A in normal pregnancy relationship to fetal and maternal characteristics.
  • Insulin-like growth factor binding protein-5 is cleaved by physiological concentrations of thrombin. Endocrinology 139, 1708-14.

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  • Pregnancy & Childbirth (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The invention relates to pregnancy-associated plasma protein-E (PAPP-E).

Description

Pregnancy-associated Plasma-Protein-E (PAPP-E) Pregnancy-associated Plasma-Protein-E (PAPP-E)

Die Erfindung betrifft das Pregnancy-associated Plasma-Pro- tein-E (PAPP-E) .The invention relates to the Pregnancy-associated Plasma-Protein-E (PAPP-E).

Eine Aufstellung der in der folgenden Schilderung des Standes der Technik in Bezug genommenen Literaturstellen mit genaueren bibliographischen Angaben findet sich am Ende dieser Beschreibung.A list of the literature references referred to in the following description of the prior art with more precise bibliographical information can be found at the end of this description.

Mit immunologischen Methoden wurden im humanen maternalen Serum der letzten Schwangerschaftswochen vier Plasmaproteine nachgewiesen und Pregnancy-associa ted Plasma Proteins (PAPP- A, -B, -C und -D) genannt [Gall 1972, Lin 1974]. Während es sich bei PAPP-C und -D um das schwangerschaftsspezifische ßι~ Glykoprotein beziehungsweise das plazentale Laktogen handelte [Lin 1974, Bohn 1971], waren PAPP-A und -B neue Proteine. Im Gegensatz zu PAPP-B, das als ein 1300 kDa großes Oktamer aus vermutlich identischen, 74 kDa schweren Untereinheiten . beschrieben wurde [Bossi 1993], ist PÄPP-A ein Monomer und bildet einen etwa 800 kDa schweren disulfidverbrückten 2:2- Komplex mit der stark glykosylierten Proform des EosinophilUsing immunological methods, four plasma proteins were detected in human maternal serum in the last few weeks of pregnancy and named Pregnancy-associated Plasma Proteins (PAPP-A, -B, -C and -D) [Gall 1972, Lin 1974]. While PAPP-C and -D were the pregnancy-specific β ~ glycoprotein or the placental lactogen [Lin 1974, Bohn 1971], PAPP-A and -B were new proteins. In contrast to PAPP-B, which acts as a 1300 kDa octamer from presumably identical, 74 kDa subunits. [Bossi 1993], PÄPP-A is a monomer and forms an approximately 800 kDa disulfide-bridged 2: 2 complex with the strongly glycosylated proform of eosinophil

BESTATIGUNGSKOPIE Maj or Basic Proteins (proMBP) [Oxvig 1993] . Dieser Komplex ist 4-6 Wochen nach der Konzeption im maternalen Serum nachweisbar und erreicht gegen Ende der Schwangerschaft Konzentrationen von etwa 50 mg/1 [Folkersen 1981, Westergaard 1983] . Die Hauptquelle des PAPP-A/proMBP-Komplexes, der im Fetus nicht vorkommt, scheint das trophoblastische Gewebe der Plazenta zu sein [Bonno 1994] . Nach der Geburt verschwindet der Komplex aus der Zirkulation mit einer Halbwertszeit von drei bis vier Tagen [Lin 1976] . Der PAPP-A/proMBP-Komplex ist auch bei nicht schwangeren Frauen nachweisbar, und zwar in niedrigen Konzentrationen in den Granulosazellen, der Fol- likelflüssigkeit der Ovarien, in der Oviduktmucosa, der Zer- vixmucosa und dem Endometrium [Sinosich 1984, Sjöberg 1984 und 1986] . Ebenso sind niedrige Konzentrationen beim Mann ge- messen worden, nämlich in Testis und Seminalplasma [Klopper 1985] .BESTATIGUNGSKOPIE Maj or Basic Proteins (proMBP) [Oxvig 1993]. This complex is detectable in the maternal serum 4-6 weeks after conception and reaches concentrations of around 50 mg / l towards the end of pregnancy [Folkersen 1981, Westergaard 1983]. The main source of the PAPP-A / proMBP complex, which does not occur in the fetus, appears to be the trophoblastic tissue of the placenta [Bonno 1994]. After birth, the complex disappears from circulation with a half-life of three to four days [Lin 1976]. The PAPP-A / proMBP complex is also detectable in women who are not pregnant, namely in low concentrations in the granulosa cells, the folic fluid of the ovaries, in the oviduct mucosa, the cervical mucosa and the endometrium [Sinosich 1984, Sjöberg 1984 and 1986]. Low concentrations have also been measured in men, namely in testis and seminal plasma [Klopper 1985].

In den letzten Jahren wurde durch zahlreiche Studien dokumentiert, daß PAPP-A als diagnostischer Marker für fetale Triso- mie 21 (Down-Syndrom) im maternalen Serum des ersten Trimesters der Schwangerschaft genutzt werden kann. Im Vergleich zu normal verlaufenden Schwangerschaften ist die PAPP-A/proMBP- Konzentration, gemessen zwischen der sechsten und vierzehnten Schwangerschaftswoche, um 50 bis 77 Prozent reduziert [Pandya 1995] . Je nach Kombination mit weiteren Markern, insbesondere der freien ß-Untereinheit des humanen Choriongonadotropin (ßhCG) , der Ultraschallmessung der fetalen Nackentransparenz und dem Alter der Schwangeren, können 76 bis 87% der Schwangerschaften mit Trisomie 21 im ersten Trimester nicht-invasiv erkannt werden [u.a. De Graaf 1999]. Entsprechendes gilt für die Triso ien 13, 18 und 22 [Bersinger 1994, Wheeler 1996, Biagotti 1998] . 1993 und 1994 erfolgten die Lokalisierung des PAPP-A Genes auf Chromosom 9 und die Klonierung der vollständigen cDNA- Sequenz [Silahtaroglu 1993, Kristensen 1994] . Das 1547 Aminosäuren große PAPP-A ensteht aus einem größeren Propeptid und umfaßt 82 Cysteinreste, die alle verbrückt sind, sowie 14 potentielle N-Glykosylierungsstellen und 7 mögliche Stellen für Glykosaminoglykan-Gruppen [Kristensen 1994] . Obwohl PAPP- A insgesamt keine Homologie zu anderen Proteinen besitzt, existieren C-terminal fünf jeweils ungefähr 60 Reste umfassende Motive, die ähnlich in Komplement regulierenden Proteinen und Selektinen vorkommen [Kristensen 1987 und 1994, Reid 1989] . Darüber hinaus beinhaltet die PAPP-A Sequenz drei etwa 30 Reste lange Motive, die mit den Lin-notch Motiven in homeo- tischen Proteinen der frühen Gewebsdifferenzierung bei C. elegans, D. Melanogaster und X. laevis verwandt sind [Kristensen 1994] .In recent years, numerous studies have documented that PAPP-A can be used as a diagnostic marker for fetal trisomy 21 (Down syndrome) in the maternal serum of the first trimester of pregnancy. Compared to normal pregnancies, the PAPP-A / proMBP concentration, measured between the sixth and fourteenth week of pregnancy, is reduced by 50 to 77 percent [Pandya 1995]. Depending on the combination with other markers, in particular the free ß subunit of human chorionic gonadotropin (ßhCG), the ultrasound measurement of the fetal nuchal translucency and the age of the pregnant woman, 76 to 87% of pregnancies with trisomy 21 can be recognized non-invasively in the first trimester [ including De Graaf 1999]. The same applies to Triso ien 13, 18 and 22 [Bersinger 1994, Wheeler 1996, Biagotti 1998]. In 1993 and 1994 the PAPP-A gene was located on chromosome 9 and the complete cDNA sequence was cloned [Silahtaroglu 1993, Kristensen 1994]. The 1547 amino acid PAPP-A consists of a larger propeptide and comprises 82 cysteine residues, which are all bridged, as well as 14 potential N-glycosylation sites and 7 possible sites for glycosaminoglycan groups [Kristensen 1994]. Although PAPP-A has no overall homology to other proteins, there are five C-terminal motifs, each comprising about 60 residues, which are similar in complement-regulating proteins and selectins [Kristensen 1987 and 1994, Reid 1989]. In addition, the PAPP-A sequence contains three motifs of about 30 residues in length, which are related to the Lin-notch motifs in homeotic proteins of early tissue differentiation in C. elegans, D. Melanogaster and X. laevis [Kristensen 1994].

Zudem verfügt PAPP-A über ein potentielles Zinkbindungsmotiv mit potentiellem Met-Turn, wie es in den Astacinen, Ser- ralysinen, Adamalysinen einschließlich einiger ADAMs und Ma- trixmetalloproteinasen vorkommt [Stöcker 1995, Bode 1996] . Vor kurzem wurde gezeigt, daß proteolytische Aktivität gegenüber dem Insulin-like Growth Factor Binding Protein-4 (IGFBP-4) besteht [Lawrence 1999]. Hierdurch würde regulato- risch in die sogenannte "IGF-Achse" eingegriffen werden. Sie umfaßt die beiden Insulin-like Growth Factors (IGF-I und - II) , die Insulin-like Growth Factor Binding Proteins (IGFBP-1 bis -6) , IGFBP-spaltende Proteinasen und die IGF-Rezeptoren (vorallem IGF-IR) [Bayes-Genis 1999] .In addition, PAPP-A has a potential zinc binding motif with a potential Met-Turn, as occurs in the astacins, serralysins, adamalysines including some ADAMs and matrix metalloproteinases [Stöcker 1995, Bode 1996]. It has recently been shown that there is proteolytic activity against insulin-like growth factor binding protein-4 (IGFBP-4) [Lawrence 1999]. This would intervene in the so-called "IGF axis" in a regulatory manner. It includes the two insulin-like growth factors (IGF-I and - II), the insulin-like growth factor binding proteins (IGFBP-1 to -6), IGFBP-cleaving proteinases and the IGF receptors (especially IGF-IR) [Bayes-Genis 1999].

Um für ihre biologische Signalwirkung zur Verfügung zu stehen, müssen die IGFs aus den Komplexen mit ihren Bindungspro- teinen freigesetzt werden. Dieses kann durch die Serinpro- teinasen Plasmin und Thrombin [Angelloz-Nicoud 1996, Zheng 1998], die Matrixmetalloproteinasen MMP-1, -2 und -3 (Kollagenase 1, Gelatinase A und Stromelysin 1) [Fowlkes 1994], sowie durch PAPP-A geschehen [Lawrence 1999] , indem diese die Bindungsproteine spalten. Anschließend können die freien IGFs an ihre Rezeptoren binden, insbesondere den IGF-IR, der als Rezeptor-Tyrosinkinase verschiedene intrazelluläre Signalwege initiiert. Diese führen schließlich zu den pleiotropen Effek- ten der IGF-Achse wie Proliferation, Differenzierung und dem Schutz vor Apoptose [Butt 1999] , aber auch zu pathobiochemis- chen Prozessen beispielsweise bei Herzerkrankungen oder Krebs [Ren 1999, Yu 1999] .In order to be available for their biological signaling action, the IGFs from the complexes with their binding pro stones are released. This can be done by the serine proteinases plasmin and thrombin [Angelloz-Nicoud 1996, Zheng 1998], the matrix metalloproteinases MMP-1, -2 and -3 (collagenase 1, gelatinase A and stromelysin 1) [Fowlkes 1994], and by PAPP- A happen [Lawrence 1999] by cleaving the binding proteins. The free IGFs can then bind to their receptors, in particular the IGF-IR, which initiates various intracellular signaling pathways as receptor tyrosine kinase. These ultimately lead to the pleiotropic effects of the IGF axis such as proliferation, differentiation and protection against apoptosis [Butt 1999], but also to pathobiochemical processes, for example in heart diseases or cancer [Ren 1999, Yu 1999].

Die Erfindung betrifft nun eine cDNA-Sequenz, die das humane Pregnancy-associated Plasma-Protein-E (PAPP-E) kodiert.The invention now relates to a cDNA sequence which encodes the human pregnancy-associated plasma protein E (PAPP-E).

Die erfindungsgemäße DNA-Sequenz umfaßt eine DNA-Sequenz, die ausgewählt ist unterThe DNA sequence according to the invention comprises a DNA sequence which is selected from

(a) der folgenden DNA-Sequenz:(a) the following DNA sequence:

tccgagggcgcccgggcaggtgttctgccaactctgagctgggctggacacgcaagaaatcc ttggttgagagggaacacctgaatcaggtgctgttggaaggagaacgttgttggctgggggc caaggttcgaagacccagagcttctccacagcatcacctctttggagtctaccccagcaggg ctgggaactacctaaggccctaccccgtgggggagcaagaaatccatcatacaggacgcagc aaaccagacactgaaggaaatgctgtgagccttgttcccccagacctgactgaaaatccagc aggactgaggggtgcagttgaagagccggctgccccatgggtaggggatagtcctattgggc aatctgagctgctgggagatgatgacgcttatctcggcaatcaaagatccaaggagtctcta ggtgaggccgggattcagaaaggctcagccatggctgccactactaccaccgccattttcac aaccctgaacgaacccaaaccagagacccaaaggaggggctgggccaagtccaggcagcgtc gccaagtgtggaagaggcgggcggaagatgggcagggagactccggtatctcttcacatttc caaccttggcccaagcattcccttaaacacagggtcaaaaagagtccaccggaggaaagcaa ccaaaatggtggagagggctcctaccgagaagcagagacctttaactcccaagtaggactgc ccatcttatacttctctgggaggcgggagcggctgctgctgcgtccagaagtgctggctgag attccccgggaggcgttcacagtggaagcctgggttaaaccggagggaggacagaacaaccc agccatcatcgcaggtgtgtttgataactgctcccacactgtcagtgacaaaggctgggccc tggggatccgctcagggaaggacaagggaaagcgggatgctcgcttcttcttctccctctgc accgaccgcgtgaagaaagccaccatcttgattagccacagtcgctaccaaccaggcacatg gacccatgtggcagccacttacgatggacggcacatggccctgtatgtggatggcactcagg tggctagcagtctagaccagtctggtcccctgaacagccccttcatggcatcttgccgctct ttgctcctggggggagacagctctgaggatgggcactatttccgtggacacctgggcacact ggttttctggtcgaccgccctgccacaaagccattttcagcacagttctcagcattcaagtg aggaggaggaagcgactgacttggtcctgacagcgagctttgagcctgtgaacacagagtgg gttccctttagagatgagaagtacccacgacttgaggttctccagggctttgagccagagcc tgagattctgtcgcctttgcagcccccactctgtgggcaaacagtctgtgacaatgtggaat tgatctcccagtacaatggatactggccccttcggggagagaaggtgatacgctaccaggtg gtgaacatctgtgatgatgagggcctaaaccccattgtgagtgaggagcagattcgtctgca gcacgaggcactgaatgaggccttcagccgctacaacatcagctggcagctgagcgtccacc aggtccacaattccaccctgcgacaccgggttgtgcttgtgaactgtgagcccagcaagatt ggcaatgaccattgtgaccccgagtgtgagcacccactcacaggctatgatgggggtgactg ccgcctgcagggccgctgctactcctggaaccgcagggatgggctctgtcacgtggagtgta acaacatgctgaacgactttgacgacggagactgctgcgacccccaggtggctgatgtgcgc aagacctgctttgaccctgactcacccaagagggcatacatgagtgtgaaggagctgaagga ggccctgcagctgaacagtactcacttcctcaacatctactttgccagctcagtgcgggaag accttgcaggtgctgccacctggccttgggacaaggacgctgtcactcacctgggtggcatt gtcctcagcccagcatattatgggatgcctggccacaccgacaccatgatccatgaagtggg acatgttctgggactctaccatgtctttaaaggagtcagtgaaagagaatcctgcaatgacc cctgcaaggagacagtgccatccatggaaacgggagacctctgtgccgacaccgcccccact cccaagagtgagctgtgccgggaaccagagcccactagtgacacctgtggcttcactcgctt cccaggggctccgttcaccaactacatgagctacacggatgataactgcactgacaacttca ctcctaaccaagtggcccgaatgcattgctatttggacctagtctatcagcagtggactgaa agcagaaagcccacccccacccccattccacctatggtcatcggacagaccaacaagtccct cactatccactggctgcctcctattagtggagttgtatatgacagggcctcaggcagcttgt gtggcgcttgcactgaagatgggacctttcgtcagtatgtgcacacagcttcctcccggcgg gtgtgtgactcctcaggttattggaccccagaggaggctgtggggcctcctgatgtggatca gccctgcgagccaagcttacaggcctggagccctgaggtccacctgtaccacatgaacatga cggtcccctgccccacagaaggctgtagcttggagctgctcttccaacacccggtccaagcc gacaccctcaccctgtgggtcacttccttcttcatggagtcctcgcaggtcctctttgacac agagatcttgctggaaaacaaggagtcagtgcacctgggccccttagacactttctgtgaca tcccactcaccatcaaactgcacgtggatgggaaggtgtcgggggtgaaagtctacaccttt gatgagaggatagagattgatgcagcactcctgacttctcagccccacagtcccttgtgctc tggctgcaggcctgtgaggtaccaggttctccgcgatcccccatttgccagtggtttgcccg tggtggtgacacattctcacaggaagttcacggacgtggaggtcacacctggacagatgtat cagtaccaagttctagctgaagctggaggagaactgggagaagcttcgcctcctctgaacca cattcatggagctccttattgtggagatgggaaggtgtcagagagactgggagaagagtgtg atgatggagaccttgtgagcggagatggctgctccaaggtgtgtgagctggaggaaggtttc aactgtgtaggagagccaagcctttgctacatgtatgagggagatggcatatgtgaaccttt tgagagaaaaaccagcattgtagactgtggcatctacactcccaaaggatacttggatcaat gggctacccgggcttactcctctcatgaagacaagaagaagtgtcctgtttccttggtaact ggagaacctcattccctaatttgcacatcataccatccagatttacccaaccaccgtcccct aactggctggtttccctgtgttgccagtgaaaatgaaactcaggatgacaggagtgaacagc cagaaggtagcctgaagaaagaggatgaggtttggctcaaagtgtgtttcaatagaccagga gaggccagagcaatttttatttttttgacaactgatggcctagttcccggagagcatcagca gccgacagtgactctctacctgaccgatgtccgtggaagcaaccactctcttggaacctatg gactgtcatgccagcataatccactgattatcaatgtgacccatcaccagäatgtccttttc caccataccacctcagtgctgccgaatttctcatccccacgggtcggcatctcagctgtggc tctaaggacatcctcccgcattggtctttcggctcccagtaactgcatctcagaggacgagg ggcagaatcatcagggacagagctgtatccatcggccctgtgggaagcaggacagctgtccg tcattgctgcttgatcatgctgatgtggtgaactgtacctctataggcccaggtctcatgaa gtgtgctatcacttgtcaaaggggatttgcccttcaggccagcagtgggcagtacatcaggc ccatgcagaaggaaattctgctcacatgttcttctgggcactgggaccagaatgtgagctgc cttcccgtggactgcggtgttcccgacccgtctttggtgaactatgcaaacttctcctgctc agagggaaccaaatttctgaaacgctgctcaatctcttgtgtcccaccagccaagctgcaag gactgagcccatggctgacatgtcttgaagatggtctctggtctctccctgaagtctactgc aagttggagtgtgatgctccccctattattctgaatgccaacttgctcctgcctcactgcct ccaggacaaccacgacgtgggcaccatctgcaaatatgaatgcaaaccagggtactatgtgg cagaaagtgcagagggtaaagtcaggaacaagctcctgaagatacaatgcctggaaggtgga atctgggagcaaggcagctgcattcctgtggtgtgtgagccaccccctcctgtgtttgaagg catgtatgaatgtaccaatggcttcagcctggacagccagtgtgtgctcaactgtaaccagg aacgtgaaaagcttcccatcctctgcactaaagagggcctgtggacccaggagtttaagttg tgtgagaatctgcaaggagaatgcccaccacccccctcagagctgaattctgtggagtacaa atgtgaacaaggatatgggattggtgcagtgtgttccccattgtgtgtaatcccccccagtg accccgtgatgctacctgagaatatcactgctgacactctggagcactggatggaacctgtc aaagtccagagcattgtgtgcactggccggcgtcaatggcacccagaccccgtcttagtcca ctgcatccagtcatgtgagcccttccaagcaaatggttggtgtgacactatcaacaaccgag cctactgccactatgacgggggagactgctgctcttccacactctcctccaagaaggtcatt ccatttgctgctgactgtgacctggatgagtgcacctgccgggaccccaaggcagaagaaaa tcagtaactgtgggaacaagcccctccctccactgcctcagaggcagtaagaaagagaggcc gacccaggaggaaacaaagggtgaatgaagaagaacaatcatgaaatggaagaaggaggaag agcatgaaggatcttataagaaatgcaagaggatattgataggtgtgaactagttcatcaag tagcccaagtaggagagaatcataggcaaaagtttctttaaagtggcagttgattaacatgg aaggggaaatatgatagatatataaggaccctccacctgcccgggcggccgctctccgagggcgcccgggcaggtgttctgccaactctgagctgggctggacacgcaagaaatcc ttggttgagagggaacacctgaatcaggtgctgttggaaggagaacgttgttggctgggggc caaggttcgaagacccagagcttctccacagcatcacctctttggagtctaccccagcaggg ctgggaactacctaaggccctaccccgtgggggagcaagaaatccatcatacaggacgcagc aaaccagacactgaaggaaatgctgtgagccttgttcccccagacctgactgaaaatccagc aggactgaggggtgcagttgaagagccggctgccccatgggtaggggatagtcctattgggc aatctgagctgctgggagatgatgacgcttatctcggcaatcaaagatccaaggagtctcta ggtgaggccgggattcagaaaggctcagccatggctgccactactaccaccgccattttcac aaccctgaacgaacccaaaccagagacccaaaggaggggctgggccaagtccaggcagcgtc gccaagtgtggaagaggcgggcggaagatgggcagggagactccggtatctcttcacatttc caaccttggcccaagcattcccttaaacacagggtcaaaaagagtccaccggaggaaagcaa ccaaaatggtggagagggctcctaccgagaagcagagacctttaactcccaagtaggactgc ccatcttatacttctctgggaggcgggagcggctgctgctgcgtccagaagtgctggctgag attccccgggaggcgttcacagtggaagcctgggttaaaccggagggaggacagaacaaccc agccatcatcgcaggtgtgtttgataactgctcccacactgtcagtgacaaaggctgggccc tggggatccgctcagggaaggacaagggaaagcgggatgctcgcttcttcttctccctctgc accgaccgcgtgaagaaagccaccatcttgattagccacagtcgctaccaaccaggcacatg gacccatgtggcagccacttacgatggacggcacatggccctgtatgtggatggcactcagg tggctagcagtctagaccagtctggtcccctgaacagccccttcatggcatcttgccgctct ttgctcctggggggagacagctctgaggatgggcactatttccgtggacacctgggcacact ggttttctggtcgaccgccctgccacaaagccattttcagcacagttctcagcattcaagtg aggaggaggaagcgactgacttggtcctgacagcgagctttgagcctgtgaacacagagtgg gttccctttagagatgagaagtacccacgacttgaggttctccagggctttgagccagagcc tgagattctgtcgcctttgcagcccccactctgtgggcaaacagtctgtgacaatgtggaat tgatctcccagtacaatggatactggccccttcggggagagaaggtgatacgctaccaggtg gtgaacatctgtgatgatgagggcctaaaccccattgtgagtgaggagcagattc gtctgca gcacgaggcactgaatgaggccttcagccgctacaacatcagctggcagctgagcgtccacc aggtccacaattccaccctgcgacaccgggttgtgcttgtgaactgtgagcccagcaagatt ggcaatgaccattgtgaccccgagtgtgagcacccactcacaggctatgatgggggtgactg ccgcctgcagggccgctgctactcctggaaccgcagggatgggctctgtcacgtggagtgta acaacatgctgaacgactttgacgacggagactgctgcgacccccaggtggctgatgtgcgc aagacctgctttgaccctgactcacccaagagggcatacatgagtgtgaaggagctgaagga ggccctgcagctgaacagtactcacttcctcaacatctactttgccagctcagtgcgggaag accttgcaggtgctgccacctggccttgggacaaggacgctgtcactcacctgggtggcatt gtcctcagcccagcatattatgggatgcctggccacaccgacaccatgatccatgaagtggg acatgttctgggactctaccatgtctttaaaggagtcagtgaaagagaatcctgcaatgacc cctgcaaggagacagtgccatccatggaaacgggagacctctgtgccgacaccgcccccact cccaagagtgagctgtgccgggaaccagagcccactagtgacacctgtggcttcactcgctt cccaggggctccgttcaccaactacatgagctacacggatgataactgcactgacaacttca ctcctaaccaagtggcccgaatgcattgctatttggacctagtctatcagcagtggactgaa agcagaaagcccacccccacccccattccacctatggtcatcggacagaccaacaagtccct cactatccactggctgcctcctattagtggagttgtatatgacaggg cctcaggcagcttgt gtggcgcttgcactgaagatgggacctttcgtcagtatgtgcacacagcttcctcccggcgg gtgtgtgactcctcaggttattggaccccagaggaggctgtggggcctcctgatgtggatca gccctgcgagccaagcttacaggcctggagccctgaggtccacctgtaccacatgaacatga cggtcccctgccccacagaaggctgtagcttggagctgctcttccaacacccggtccaagcc gacaccctcaccctgtgggtcacttccttcttcatggagtcctcgcaggtcctctttgacac agagatcttgctggaaaacaaggagtcagtgcacctgggccccttagacactttctgtgaca tcccactcaccatcaaactgcacgtggatgggaaggtgtcgggggtgaaagtctacaccttt gatgagaggatagagattgatgcagcactcctgacttctcagccccacagtcccttgtgctc tggctgcaggcctgtgaggtaccaggttctccgcgatcccccatttgccagtggtttgcccg tggtggtgacacattctcacaggaagttcacggacgtggaggtcacacctggacagatgtat cagtaccaagttctagctgaagctggaggagaactgggagaagcttcgcctcctctgaacca cattcatggagctccttattgtggagatgggaaggtgtcagagagactgggagaagagtgtg atgatggagaccttgtgagcggagatggctgctccaaggtgtgtgagctggaggaaggtttc aactgtgtaggagagccaagcctttgctacatgtatgagggagatggcatatgtgaaccttt tgagagaaaaaccagcattgtagactgtggcatctacactcccaaaggatacttggatcaat gggctacccgggcttactcctctcatgaagacaagaagaagtgtcctgtttcctt ggtaact ggagaacctcattccctaatttgcacatcataccatccagatttacccaaccaccgtcccct aactggctggtttccctgtgttgccagtgaaaatgaaactcaggatgacaggagtgaacagc cagaaggtagcctgaagaaagaggatgaggtttggctcaaagtgtgtttcaatagaccagga gaggccagagcaatttttatttttttgacaactgatggcctagttcccggagagcatcagca gccgacagtgactctctacctgaccgatgtccgtggaagcaaccactctcttggaacctatg gactgtcatgccagcataatccactgattatcaatgtgacccatcaccagäatgtccttttc caccataccacctcagtgctgccgaatttctcatccccacgggtcggcatctcagctgtggc tctaaggacatcctcccgcattggtctttcggctcccagtaactgcatctcagaggacgagg ggcagaatcatcagggacagagctgtatccatcggccctgtgggaagcaggacagctgtccg tcattgctgcttgatcatgctgatgtggtgaactgtacctctataggcccaggtctcatgaa gtgtgctatcacttgtcaaaggggatttgcccttcaggccagcagtgggcagtacatcaggc ccatgcagaaggaaattctgctcacatgttcttctgggcactgggaccagaatgtgagctgc cttcccgtggactgcggtgttcccgacccgtctttggtgaactatgcaaacttctcctgctc agagggaaccaaatttctgaaacgctgctcaatctcttgtgtcccaccagccaagctgcaag gactgagcccatggctgacatgtcttgaagatggtctctggtctctccctgaagtctactgc aagttggagtgtgatgctccccctattattctgaatgccaacttgc tcctgcctcactgcct ccaggacaaccacgacgtgggcaccatctgcaaatatgaatgcaaaccagggtactatgtgg cagaaagtgcagagggtaaagtcaggaacaagctcctgaagatacaatgcctggaaggtgga atctgggagcaaggcagctgcattcctgtggtgtgtgagccaccccctcctgtgtttgaagg catgtatgaatgtaccaatggcttcagcctggacagccagtgtgtgctcaactgtaaccagg aacgtgaaaagcttcccatcctctgcactaaagagggcctgtggacccaggagtttaagttg tgtgagaatctgcaaggagaatgcccaccacccccctcagagctgaattctgtggagtacaa atgtgaacaaggatatgggattggtgcagtgtgttccccattgtgtgtaatcccccccagtg accccgtgatgctacctgagaatatcactgctgacactctggagcactggatggaacctgtc aaagtccagagcattgtgtgcactggccggcgtcaatggcacccagaccccgtcttagtcca ctgcatccagtcatgtgagcccttccaagcaaatggttggtgtgacactatcaacaaccgag cctactgccactatgacgggggagactgctgctcttccacactctcctccaagaaggtcatt ccatttgctgctgactgtgacctggatgagtgcacctgccgggaccccaaggcagaagaaaa tcagtaactgtgggaacaagcccctccctccactgcctcagaggcagtaagaaagagaggcc gacccaggaggaaacaaagggtgaatgaagaagaacaatcatgaaatggaagaaggaggaag agcatgaaggatcttataagaaatgcaagaggatattgataggtgtgaactagttcatcaag tagcccaagtaggagagaatcataggcaaaagtttctttaaagtggcagttgatt aacatgg aaggggaaatatgatagatatataaggaccctccacctgcccgggcggccgctc

oder derem komplementären Strang,or its complementary strand,

(b) DNA-Sequenzen, die unter stringenten Bedingungen an Pro¬ teine kodierende Bereiche einer DNA-Sequenz nach '(a) oder an Fragmente einer derartigen DNA-Sequenz hybridisieren,(b) DNA sequences which hybridize under stringent conditions to Pro ¬ proteins encoding regions of a DNA sequence of '(a) or to fragments of such DNA sequence,

(c) DNA-Sequenzen, die aufgrund einer Degeneration des ge¬ netischen Codes an DNA-Sequenzen nach (a) oder (b) hy¬ bridisieren,(c) DNA sequences which due to degeneracy of the netic ge ¬ code to DNA sequences of (a) or (b) hy ¬ bridisieren,

(d) allelen Variationen und Mutationen, die sich durch Sub- stitution, Insertion oder Deletion von einzelnen oder mehre¬ ren Nucleotiden oder Inversion von einzelnen oder mehreren Nucleotidteilsequenzen der DNA-Sequenzen nach (a) bis (c) er- geben, wobei die Variationen und Mutanten isofunktionelle Expressionsprodukte kodieren .(d) allelic variations and mutations that stitution by Sub, insertion or deletion of single or several nucleotides ¬ ren or inversion of single or multiple Nucleotidteilsequenzen the DNA sequences of (a) to (c) ER give, the variations and mutants encoding isofunctional expression products.

Die Erfindung betrifft ferner eine Aminosäuresequenz , die eine Aminosäuresequenz umfaßt , welche ausgewählt ist unterThe invention further relates to an amino acid sequence comprising an amino acid sequence which is selected from

(a) der folgenden Aminosäuresequenz :(a) the following amino acid sequence:

-82 MAATTTTAIFTTLNEPKPETQR -61 -60 RG AKSRQRRQVWKRRAEDGQGDSGISSHFQP PKHSLKHRVKKSPPEESNQNGGEGSYR -1-82 MAATTTTAIFTTLNEPKPETQR -61 -60 RG AKSRQRRQVWKRRAEDGQGDSGISSHFQP PKHSLKHRVKKSPPEESNQNGGEGSYR -1

1 EAETFNSQVGLPILYFSGRRERLLLRPEVLAEIPREAFTVEAWVKPEGGQNNPAIIAGVF 601 EAETFNSQVGLPILYFSGRRERLLLRPEVLAEIPREAFTVEAWVKPEGGQNNPAIIAGVF 60

61 DNCSHTVSDKGWALGIRSGKDKGKRDARFFFSLCTDRVKKATILISHSRYQPGT THVÄA 12061 DNCSHTVSDKGWALGIRSGKDKGKRDARFFFSLCTDRVKKATILISHSRYQPGT THVÄA 120

121 TYDGRHMALYVDGTQVASS DQSGP NSPFiASCRSLLLGGDSSEDGHYFRGHLGTLVF 180121 TYDGRHMALYVDGTQVASS DQSGP NSPFiASCRSLLLGGDSSEDGHYFRGHLGTLVF 180

181 STALPQSHFQHSSQHSSEEEEATDLVLTASFEPVNTE VPFRDEKYPRLEVLQGFEPEPE 240 241 ILSPLQPPLCGQTVCDNVELISQYNGYWPLRGEKVIRYQVVNICDDEGLNPIVSEEQIRL 300181 STALPQSHFQHSSQHSSEEEEATDLVLTASFEPVNTE VPFRDEKYPRLEVLQGFEPEPE 240 241 ILSPLQPPLCGQTVCDNVELISQYNGYWPLRGEKVIRYQVVNICDDEGLNPIVSEEQIRL 300

301 QHEALNEAFSRYNIS QLSVHQVHNSTLRHRVVLVNCEPSKIGNDHCDPECEHPLTGYDG 360301 QHEALNEAFSRYNIS QLSVHQVHNSTLRHRVVLVNCEPSKIGNDHCDPECEHPLTGYDG 360

361 GDCRLQGRCYSWNRRDGLCHVECNNMLNDFDDGDCCDPQVADVRKTCFDPDSPKRAYMSV 420361 GDCRLQGRCYSWNRRDGLCHVECNNMLNDFDDGDCCDPQVADVRKTCFDPDSPKRAYMSV 420

421 KELKEALQLNSTHFLNIYFASSVRED AGAATWPWDKDAVTHLGGIV SPAYYGMPGHTD 480421 KELKEALQLNSTHFLNIYFASSVRED AGAATWPWDKDAVTHLGGIV SPAYYGMPGHTD 480

481 TMIHEVGHVLGLYHVFKGVSERESCNDPCKETVPSMETGDLCADTAPTPKSELCREPEPT 540 541 SDTCGFTRFPGAPFTNYMSYTDDNCTDNFTPNQVARMHCYLDLVYQQWTESRKPTPTPIP 600481 TMIHEVGHVLGLYHVFKGVSERESCNDPCKETVPSMETGDLCADTAPTPKSELCREPEPT 540 541 SDTCGFTRFPGAPFTNYMSYTDDNCTDNFTPNQVARMHCYLDLVYQQWTESRKPTPTPIP 600

601 PMVIGQTNKSLTIHWLPPISG VYDRASGSLCGACTEDGTFRQYVHTASSRRVCDSSGYW 660601 PMVIGQTNKSLTIHWLPPISG VYDRASGSLCGACTEDGTFRQYVHTASSRRVCDSSGYW 660

661 TPEEAVGPPDVDQPCEPSLQAWSPEVHLYHMNMTVPCPTEGCSLELLFQHPVQADTLTLW 720661 TPEEAVGPPDVDQPCEPSLQAWSPEVHLYHMNMTVPCPTEGCSLELLFQHPVQADTLTLW 720

721 VTSFFMESSQVLFDTEILLENKESVHLGPLDTFCDIPLTIKLHVDGKVSGVKVYTFDERI 780721 VTSFFMESSQVLFDTEILLENKESVHLGPLDTFCDIPLTIKLHVDGKVSGVKVYTFDERI 780

781 EIDAALLTSQPHSPLCSGCRPVRYQVLRDPPFASGLPVVVTHSHRKFTDVEVTPGQMYQY 840 841 QVLAEAGGELGEASPPLNHIHGAPYCGDGKVSERLGEECDDGDLVSGDGCSKVCELEEGF 900781 EIDAALLTSQPHSPLCSGCRPVRYQVLRDPPFASGLPVVVTHSHRKFTDVEVTPGQMYQY 840 841 QVLAEAGGELGEASPPLNHIHGAPYCGDGKVSERLGEECDDGDLVSGDGCSKVCELEEGF

901 NCVGEPSLCYMYEGDGICEPFERKTSIVDCGIYTPKGYLDQWÄTRAYSSHEDKKKCPVS 960901 NCVGEPSLCYMYEGDGICEPFERKTSIVDCGIYTPKGYLDQWÄTRAYSSHEDKKKCPVS 960

961 VTGEPHSLICTSYHPDLPNHRPLTGWFPCVASENETQDDRSEQPEGSLKKEDEVWLKVCF 1020961 VTGEPHSLICTSYHPDLPNHRPLTGWFPCVASENETQDDRSEQPEGSLKKEDEVWLKVCF 1020

1021 NRPGEARAIFIFLTTDGLVPGEHQQPTVTLYLTDVRGSNHSLGTYG SCQHNPLIINVTH 10801021 NRPGEARAIFIFLTTDGLVPGEHQQPTVTLYLTDVRGSNHSLGTYG SCQHNPLIINVTH 1080

1081 HQNVLFHHTTSVLPNFSSPRVGISAVALRTSSRIGLSAPSNCISEDEGQNHQGQSCIHRP 1140 1141 CGKQDSCPSLLLDHADVVNCTSIGPGLMKCAITCQRGFALQASSGQYIRPMQKEILLTCS 12001081 HQNVLFHHTTSVLPNFSSPRVGISAVALRTSSRIGLSAPSNCISEDEGQNHQGQSCIHRP 1140 1141 CGKQDSCPSLLLDHADVVNCTSIGPGLMKCAITCQRGFALQASSGQYIRPMQKEILLTCS 1200

1201 SGHWDQNVSCLPVDCGVPDPSLVNYANFSCSEGTKFLKRCSISCVPPAKLQGLSP LTCL 12601201 SGHWDQNVSCLPVDCGVPDPSLVNYANFSCSEGTKFLKRCSISCVPPAKLQGLSP LTCL 1260

1261 EDGLWSLPEVYCKLECDAPPIILNANLLLPHCLQDNHDVGTICKYECKPGYYVÄESAEGK 13201261 EDGLWSLPEVYCKLECDAPPIILNANLLLPHCLQDNHDVGTICKYECKPGYYVÄESAEGK 1320

1321 VRNKL IQCLEGGIWEQGSCIPVVCEPPPPVFEGMYECTNGFSLDSQCVLNCNQEREKL 13801321 VRNKL IQCLEGGIWEQGSCIPVVCEPPPPVFEGMYECTNGFSLDSQCVLNCNQEREKL 1380

1381 PILCTKEGLWTQEFKLCENLQGECPPPPSELNSVEYKCEQGYGIGAVCSPLCVIPPSDPV 1440 1441 MLPENITADTLEH MEPVKVQSIVCTGRRQ HPDPV VHCIQSCEPFQANGWCDTINNRA 15001381 PILCTKEGLWTQEFKLCENLQGECPPPPSELNSVEYKCEQGYGIGAVCSPLCVIPPSDPV 1440 1441 MLPENITADTLEH MEPVKVQSIVCTGRRQ HPDPV VHCIQSCEPFQANGWCDTINNRA 1500

1501 YCHYDGGDCCSSTLSSKKVIPFAADCDLDECTCRDPKAEENQ1501 YCHYDGGDCCSSTLSSKKVIPFAADCDLDECTCRDPKAEENQ

(b) einer Aminosäuresequenz , bei der es sich um eine allele isofunktionelle Variante der in (a) definierten Aminosäurese- quenz handelt ,(b) an amino acid sequence which is an allelic isofunctional variant of the amino acid sequence defined in (a),

(c) einer Mutante der in (a) oder (b) definierten Aminosäuresequenz , bei der ein oder mehrere Aminosäurerest (e) deletiert und/oder ersetzt und/oder insertiert und/oder eine oder mehrere Aminosäureteilsequenz (en) invertiert ist/sind und welche isofunktionell ist,(c) a mutant of the amino acid sequence defined in (a) or (b), in which one or more amino acid residues (e) are deleted and / or replaced and / or inserted and / or one or several amino acid partial sequence (s) is / are inverted and which is isofunctional,

(d) einer Aminosäuresequenz, an deren C-Terminus und/oder N- Terminus eine Aminosäuresequenz fusioniert ist, wobei das sich ergebende Fusionsprotein isofunktionell ist und/oder die zusätzlichen C-terminalen oder N-terminalen Aminosäuresequenzen leicht abgespalten werden können.(d) an amino acid sequence at whose C-terminus and / or N-terminus an amino acid sequence is fused, the resulting fusion protein being isofunctional and / or the additional C-terminal or N-terminal amino acid sequences can be easily cleaved off.

Ferner umfaßt die Erfindung polyklonale oder monoklonale Antikörper gegen die obigen Aminosäuresequenzen sowie die Verwendung der obigen DNA- und/oder Aminosäuresequenzen und/oder der obigen Antikörper in einem Assay zur humangenetischen Diagnostik, insbesondere zur Bestimmung von Trisomie 13, 18, 21 oder 22, sowie die Verwendung der obigen DNA- und/oder Aminosäuresequenzen zum Auffinden von Antagonisten gegen PAPP-E.The invention further encompasses polyclonal or monoclonal antibodies against the above amino acid sequences and the use of the above DNA and / or amino acid sequences and / or the above antibodies in an assay for human genetic diagnostics, in particular for determining trisomy 13, 18, 21 or 22, and the use of the above DNA and / or amino acid sequences to find antagonists against PAPP-E.

Weitere vorteilhafte und/oder bevorzugte Ausführungsformen der Erfindung sind Gegenstand der Unteransprüche.Further advantageous and / or preferred embodiments of the invention are the subject of the dependent claims.

Im folgenden wird die Erfindung ohne Beschränkung' anhand von Ausführungsbeispielen und unter Bezugnahme auf die Abbildungen detaillierter beschrieben.In the following, the invention is not limited 'by means of embodiments and with reference to the figures described in more detail.

Durch Genbankrecherche mit den BLAST-Programmen am NCBI [Altschul, 1997] wurde nach neuen cDNAs für Proteine mit Zinkbindungsmotiv gesucht. Dabei wurde ein zirka 300 bp großes Expressed Sequence Tag (EST) gefunden (gi 2020543) . Dieses kodiert ein Proteinfragment mit dem vollständig konservierten Zinkbindungsmotiv der Metzinkine [Bode 1996] und besitzt hohe Homologie zu dem Pregnancy-associa ted Plasma Protein-A (PAPP-A) .Genebank research with the BLAST programs at NCBI [Altschul, 1997] looked for new cDNAs for proteins with a zinc binding motif. An Expressed Sequence Tag (EST) of around 300 bp was found (gi 2020543). This encodes a protein fragment with the completely preserved zinc binding motif of the Metzinkine [Bode 1996] and has high homology to the Pregnancy-associated Plasma Protein-A (PAPP-A).

Die Klonierung dieses cDNA Fragmentes erfolgte durch RT-PCR [Sambrook, 1989] . Hierzu wurde RNA aus Plazentagewebe isoliert (RNeasy Total RNA System, Qiagen) , revers transkribiert (Superscript II RNase H" Reverse Transcriptase, Life Technologies), mit den PrimernThis cDNA fragment was cloned by RT-PCR [Sambrook, 1989]. For this, RNA was isolated from placental tissue (RNeasy Total RNA System, Qiagen), reverse transcribed (Superscript II RNase H " Reverse Transcriptase, Life Technologies), with the primers

5' -tgaaggagctgaaggaggccctgc-3' und 5' -cggtgtcggcacagaggtctcccg-3' amplifiziert (Taq DNA Polymerase, Röche) und mittels TA- Cloning kloniert (TOPO TA Cloning Kit, Invitrogen) . Anschließende 5'- und 3' -RACE-Experimente mit diesen genspezifischen Primern, Marathon-Ready-Placenta-cDNA (Clontech) , dem Advantage-2-Polymerase-Mix (Clontech) und dem TOPO-XL-PCR Cloning-Kit (Invitrogen) führte zur Klonierung der vollständigen cDNA einschließlich flankierendem 5'- und 3'- Bereich [Abb. 1] . Die abgeleitete, 1542 Aminosäuren umfassende Sequenz des reifen Proteins wurde "PAPP-E" genannt, da sie im Vergleich zu PAPP-A eine 62 prozentige Homologie mit 44 Prozent identischen Aminosäuren, eine konservierte Anordnung der rund 80 Cysteinreste und eine konservierte Domänenstruktur besitzt [Abb. 2, Abb. 3] . Ferner wurde das PAPP-E- Gen durch Radiation-Hybrid-Mapping [Cox 1990] mit dem Gene- Bridge4-Panel (Research Genetics) und den Primern5 '-tgaaggagctgaaggaggccctgc-3' and 5 '-cggtgtcggcacagaggtctcccg-3' amplified (Taq DNA polymerase, Röche) and cloned using TA cloning (TOPO TA Cloning Kit, Invitrogen). Subsequent 5 'and 3' RACE experiments with these gene-specific primers, marathon-ready placenta cDNA (Clontech), the Advantage 2 polymerase mix (Clontech) and the TOPO-XL-PCR cloning kit (Invitrogen ) led to the cloning of the complete cDNA including the flanking 5 'and 3' region [Fig. 1] . The derived sequence of the mature protein, comprising 1542 amino acids, was called "PAPP-E" because, in comparison to PAPP-A, it has a 62 percent homology with 44 percent identical amino acids, a conserved arrangement of around 80 cysteine residues and a conserved domain structure [Fig , 2, Fig. 3]. Furthermore, the PAPP-E gene was obtained by radiation hybrid mapping [Cox 1990] with the Gene Bridge4 panel (Research Genetics) and the primers

5' -agcccagcatattatgggatgcctggcc-3' und 5' -ggtgtcggcacagaggtctcccgtttcc-3' auf Chromosom 1 im Bereich der Bande q23-25 lokalisiert [Abb. 5].5'-agcccagcatattatgggatgcctggcc-3 'and 5' -ggtgtcggcacagaggtctcccgtttcc-3 'located on chromosome 1 in the region of band q23-25 [Fig. 5].

Durch RNA-Array-Hybridisierung konnte gezeigt werden, daß PAPP-E sehr spezifisch in plazentalem Gewebe exprimiert wird [Abb. 4]. Dieser Nachweis erfolgte durch Biotinylierung des klonierten PAPP-E-cDNA-Framentes (North2South Biotin Random Prime Kit, Pierce) , Hybridisierung des MTE-Array-2 (Pierce) und Detektion mit dem North2South-Chemiluminescent-Hybridiza- tion-and-Detection-Kit (Pierce), CL-XPosure-X-ray Film (Pierce) und Eukobrom-Entwickler und Superfix-Fixierlösung (Tete- nal) .RNA array hybridization showed that PAPP-E is expressed very specifically in placental tissue [Fig. 4]. This was demonstrated by biotinylation of the cloned PAPP-E cDNA fragment (North2South Biotin Random Prime Kit, Pierce), hybridization of the MTE-Array-2 (Pierce) and detection with the North2South-Chemiluminescent-Hybridization-and-Detection- Kit (Pierce), CL-XPosure-X-ray film (Pierce) and eukobrom developer and Superfix fixative (Tetenal).

Zusammengefaßt offenbart bzw. umfaßt die Erfindung somit das humane Pregnancy-associated Plasma-Protein-E (PAPP-E), die zugehörige cDNA, DNA und RNA, sowie die chromosomale Lokalisierung auf dem Chromosom lq23-25, die Darstellung des Proteins und abgeleiteter Peptide aus Zellkulturen durch Anwendung von Rekombinationstechniken sowie die Isolierung aus hu- manen Seren, den Einsatz der DNA und des Proteins sowie jeweiliger Fragmente sowie von Peptid- und Nucleinsäure-Anta- gonisten zu therapeutischen Zwecken, diagnostische Assays zum Nachweis des Proteins und der DNA, sowie natürlich vorkommende Mutationen. In summary, the invention thus discloses or comprises the human pregnancy-associated plasma protein E (PAPP-E), the associated cDNA, DNA and RNA, and the chromosomal localization on the chromosome lq23-25, the display of the protein and derived peptides from cell cultures through the use of recombination techniques and isolation from human sera, the use of DNA and the protein and respective fragments as well as peptide and nucleic acid antagonists for therapeutic purposes, diagnostic assays for the detection of the protein and the DNA, and naturally occurring mutations.

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Claims

Patentansprüche claims 1. DNA-Sequenz, die eine DNA-Sequenz umfaßt, welche ausgewählt ist unter1. DNA sequence which comprises a DNA sequence which is selected from (a) der folgenden DNA-Sequenz:(a) the following DNA sequence: tccgagggcgcccgggcaggtgttctgccaactctgagctgggctggacacgcaagaaatcc ttggttgagagggaacacctgaatcaggtgctgttggaaggagaacgttgttggctgggggc caaggttcgaagacccagagcttctccacagcatcacctctttggagtctaccccagcaggg ctgggaactacctaaggccctaccccgtgggggagcaagaaatccatcatacaggacgcagc aaaccagacactgaaggaaatgctgtgagccttgttcccccagacctgactgaaaatccagc aggactgaggggtgcagttgaagagccggctgccccatgggtaggggatagtcctattgggc aatctgagctgctgggagatgatgacgcttatctcggcaatcaaagatccaaggagtctcta ggtgaggccgggattcagaaaggctcagccatggctgccactactaccaccgccattttcac aaccctgaacgaacccaaaccagagacccaaaggaggggctgggccaagtccaggcagcgtc gccaagtgtggaagaggcgggcggaagatgggcagggagactccggtatctcttcacatttc caaccttggcccaagcattcccttaaacacagggtcaaaaagagtccaccggaggaaagcaa ccaaaatggtggagagggctcctaccgagaagcagagacctttaactcccaagtaggactgc ccatcttatacttctctgggaggcgggagcggctgctgctgcgtccagaagtgctggctgag attccccgggaggcgttcacagtggaagcctgggttaaaccggagggaggacagaacaaccc agccatcatcgcaggtgtgtttgataactgctcccacactgtcagtgacaaaggctgggccc tggggatccgctcagggaaggacaagggaaagcgggatgctcgcttcttcttctccctctgc accgaccgcgtgaagaaagccaccatcttgattagccacagtcgctaccaaccaggcacatg gacccatgtggcagccacttacgatggacggcacatggccctgtatgtggatggcactcagg tggctagcagtctagaccagtctggtcccctgaacagccccttcatggcatcttgccgctct ttgctcctggggggagacagctctgaggatgggcactatttccgtggacacctgggcacact ggttttctggtcgaccgccctgccacaaagccattttcagcacagttctcagcattcaagtg aggaggaggaagcgactgacttggtcctgacagcgagctttgagcctgtgaacacagagtgg gttccctttagagatgagaagtacccacgacttgaggttctccagggctttgagccagagcc tgagattctgtcgcctttgcagcccccactctgtgggcaaacagtctgtgacaatgtggaat tgatctcccagtacaatggatactggccccttcggggagagaaggtgatacgctaccaggtg gtgaacatctgtgatgatgagggcctaaaccccattgtgagtgaggagcagattcgtctgca gcacgaggcactgaatgaggccttcagccgctacaacatcagctggcagctgagcgtccacc aggtccacaattccaccctgcgacaccgggttgtgcttgtgaactgtgagcccagcaagatt ggcaatgaccattgtgaccccgagtgtgagcacccactcacaggctatgatgggggtgactg ccgcctgcagggccgctgctactcctggaaccgcagggatgggctctgtcacgtggagtgta acaacatgctgaacgactttgacgacggagactgctgcgacccccaggtggctgatgtgcgc aagacctgctttgaccctgactcacccaagagggcatacatgagtgtgaaggagctgaagga ggccctgcagctgaacagtactcacttcctcaacatctactttgccagctcagtgcgggaag accttgcaggtgctgccacctggccttgggacaaggacgctgtcactcacctgggtggcatt gtcctcagcccagcatattatgggatgcctggccacaccgacaccatgatccatgaagtggg acatgttctgggactctaccatgtctttaaaggagtcagtgaaagagaatcctgcaatgacc cctgcaaggagacagtgccatccatggaaacgggagacctctgtgccgacaccgcccccact cccaagagtgagctgtgccgggaaccagagcccactagtgacacctgtggcttcactcgctt cccaggggctccgttcaccaactacatgagctacacggatgataactgcactgacaacttca ctcctaaccaagtggcccgaatgcattgctatttggacctagtctatcagcagtggactgaa agcagaaagcccacccccacccccattccacctatggtcatcggacagaccaacaagtccct cactatccactggctgcctcctattagtggagttgtatatgacagggcctcaggcagcttgt gtggcgcttgcactgaagatgggacctttcgtcagtatgtgcacacagcttcctcccggcgg gtgtgtgactcctcaggttattggaccccagaggaggctgtggggcctcctgatgtggatca gccctgcgagccaagcttacaggcctggagccctgaggtccacctgtaccacatgaacatga cggtcccctgccccacagaaggctgtagcttggagctgctcttccaacacccggtccaagcc gacaccctcaccctgtgggtcacttccttcttcatggagtcctcgcaggtcctctttgacac agagatcttgctggaaaacaaggagtcagtgcacctgggccccttagacactttctgtgaca tcccactcaccatcaaactgcacgtggatgggaaggtgtcgggggtgaaagtctacaccttt gatgagaggatagagattgatgcagcactcctgacttctcagccccacagtcccttgtgctc tggctgcaggcctgtgaggtaccaggttctccgcgatcccccatttgccagtggtttgcccg tggtggtgacacattctcacaggaagttcacggacgtggaggtcacacctggacagatgtat cagtaccaagttctagctgaagctggaggagaactgggagaagcttcgcctcctctgaacca cattcatggagctccttattgtggagatgggaaggtgtcagagagactgggagaagagtgtg atgatggagaccttgtgagcggagatggctgctccaaggtgtgtgagctggaggaaggtttc aactgtgtaggagagccaagcctttgctacatgtatgagggagatggcatatgtgaaccttt tgagagaaaaaccagcattgtagactgtggcatctacactcccaaaggatacttggatcaat gggctacccgggcttactcctctcatgaagacaagaagaagtgtcctgtttccttggtaact ggagaacctcattccctaatttgcacatcataccatccagatttacccaaccaccgtcccct aactggctggtttccctgtgttgccagtgaaaatgaaactcaggatgacaggagtgaacagc cagaaggtagcctgaagaaagaggatgaggtttggctcaaagtgtgtttcaatagaccagga gaggccagagcaatttttatttttttgacaactgatggcctagttcccggagagcatcagca gccgacagtgactctctacctgaccgatgtccgtggaagcaaccactctcttggaacctatg gactgtcatgccagcataatccactgattatcaatgtgacccatcaccagaatgtccttttc caccataccacctcagtgctgccgaatttctcatccccacgggtcggcatctcagctgtggc tctaaggacatcctcccgcattggtctttcggctcccagtaactgcatctcagaggacgagg ggcagaatcatcagggacagagctgtatccatcggccctgtgggaagcaggacagctgtccg tcattgctgcttgatcatgctgatgtggtgaactgtacctctataggcccaggtctcatgaa gtgtgctatcacttgtcaaaggggatttgcccttcaggccagcagtgggcagtacatcaggc ccatgcagaaggaaattctgctcacatgttcttctgggcactgggaccagaatgtgagctgc cttcccgtggactgcggtgttcccgacccgtctttggtgaactatgcaaacttctcctgctc agagggaaccaaatttctgaaacgctgctcaatctcttgtgtcccaccagccaagctgcaag gactgagcccatggctgacatgtcttgaagatggtctctggtctctccctgaagtctactgc aagttggagtgtgatgctccccctattattctgaatgccaacttgctcctgcctcactgcct ccaggacaaccacgacgtgggcaccatctgcaaatatgaatgcaaaccagggtactatgtgg cagaaagtgcagagggtaaagtcaggaacaagctcctgaagatacaatgcctggaaggtgga atctgggagcaaggcagctgcattcctgtggtgtgtgagccaccccctcctgtgtttgaagg catgtatgaatgtaccaatggcttcagcctggacagccagtgtgtgctcaactgtaaccagg aacgtgaaaagcttcccatcctctgcactaaagagggcctgtggacccaggagtttaagttg tgtgagaatctgcaaggagaatgcccaccacccccctcagagctgaattctgtggagtacaa atgtgaacaaggatatgggattggtgcagtgtgttccccattgtgtgtaatcccccccagtg accccgtgatgctacctgagaatatcactgctgacactctggagcactggatggaacctgtc aaagtccagagcattgtgtgcactggccggcgtcaatggcacccagaccccgtcttagtcca ctgcatccagtcatgtgagcccttccaagcaaatggttggtgtgacactatcaacaaccgag cctactgccactatgacgggggagactgctgctcttccacactctcctccaagaaggtcatt ccatttgctgctgactgtgacctggatgagtgcacctgccgggaccccaaggcagaagaaaa tcagtaactgtgggaacaagcccctccctccactgcctcagaggcagtaagaaagagaggcc gacccaggaggaaacaaagggtgaatgaagaagaacaatcatgaaatggaagaaggaggaag agcatgaaggatcttataagaaatgcaagaggatattgataggtgtgaactagttcatcaag tagcccaagtaggagagaatcataggcaaaagtttctttaaagtggcagttgattaacatgg aaggggaaatatgatagatatataaggaccctccacctgcccgggcggccgctctccgagggcgcccgggcaggtgttctgccaactctgagctgggctggacacgcaagaaatcc ttggttgagagggaacacctgaatcaggtgctgttggaaggagaacgttgttggctgggggc caaggttcgaagacccagagcttctccacagcatcacctctttggagtctaccccagcaggg ctgggaactacctaaggccctaccccgtgggggagcaagaaatccatcatacaggacgcagc aaaccagacactgaaggaaatgctgtgagccttgttcccccagacctgactgaaaatccagc aggactgaggggtgcagttgaagagccggctgccccatgggtaggggatagtcctattgggc aatctgagctgctgggagatgatgacgcttatctcggcaatcaaagatccaaggagtctcta ggtgaggccgggattcagaaaggctcagccatggctgccactactaccaccgccattttcac aaccctgaacgaacccaaaccagagacccaaaggaggggctgggccaagtccaggcagcgtc gccaagtgtggaagaggcgggcggaagatgggcagggagactccggtatctcttcacatttc caaccttggcccaagcattcccttaaacacagggtcaaaaagagtccaccggaggaaagcaa ccaaaatggtggagagggctcctaccgagaagcagagacctttaactcccaagtaggactgc ccatcttatacttctctgggaggcgggagcggctgctgctgcgtccagaagtgctggctgag attccccgggaggcgttcacagtggaagcctgggttaaaccggagggaggacagaacaaccc agccatcatcgcaggtgtgtttgataactgctcccacactgtcagtgacaaaggctgggccc tggggatccgctcagggaaggacaagggaaagcgggatgctcgcttcttcttctc cctctgc accgaccgcgtgaagaaagccaccatcttgattagccacagtcgctaccaaccaggcacatg gacccatgtggcagccacttacgatggacggcacatggccctgtatgtggatggcactcagg tggctagcagtctagaccagtctggtcccctgaacagccccttcatggcatcttgccgctct ttgctcctggggggagacagctctgaggatgggcactatttccgtggacacctgggcacact ggttttctggtcgaccgccctgccacaaagccattttcagcacagttctcagcattcaagtg aggaggaggaagcgactgacttggtcctgacagcgagctttgagcctgtgaacacagagtgg gttccctttagagatgagaagtacccacgacttgaggttctccagggctttgagccagagcc tgagattctgtcgcctttgcagcccccactctgtgggcaaacagtctgtgacaatgtggaat tgatctcccagtacaatggatactggccccttcggggagagaaggtgatacgctaccaggtg gtgaacatctgtgatgatgagggcctaaaccccattgtgagtgaggagcagattcgtctgca gcacgaggcactgaatgaggccttcagccgctacaacatcagctggcagctgagcgtccacc aggtccacaattccaccctgcgacaccgggttgtgcttgtgaactgtgagcccagcaagatt ggcaatgaccattgtgaccccgagtgtgagcacccactcacaggctatgatgggggtgactg ccgcctgcagggccgctgctactcctggaaccgcagggatgggctctgtcacgtggagtgta acaacatgctgaacgactttgacgacggagactgctgcgacccccaggtggctgatgtgcgc aagacctgctttgaccctgactcacccaagagggcatacatgagtgtgaaggagctgaagga ggccctgcagctgaacagtactcacttcctcaacatctactttgccagctcagtgcgggaag accttgcaggtgctgccacctggccttgggacaaggacgctgtcactcacctgggtggcatt gtcctcagcccagcatattatgggatgcctggccacaccgacaccatgatccatgaagtggg acatgttctgggactctaccatgtctttaaaggagtcagtgaaagagaatcctgcaatgacc cctgcaaggagacagtgccatccatggaaacgggagacctctgtgccgacaccgcccccact cccaagagtgagctgtgccgggaaccagagcccactagtgacacctgtggcttcactcgctt cccaggggctccgttcaccaactacatgagctacacggatgataactgcactgacaacttca ctcctaaccaagtggcccgaatgcattgctatttggacctagtctatcagcagtggactgaa agcagaaagcccacccccacccccattccacctatggtcatcggacagaccaaca agtccct cactatccactggctgcctcctattagtggagttgtatatgacagggcctcaggcagcttgt gtggcgcttgcactgaagatgggacctttcgtcagtatgtgcacacagcttcctcccggcgg gtgtgtgactcctcaggttattggaccccagaggaggctgtggggcctcctgatgtggatca gccctgcgagccaagcttacaggcctggagccctgaggtccacctgtaccacatgaacatga cggtcccctgccccacagaaggctgtagcttggagctgctcttccaacacccggtccaagcc gacaccctcaccctgtgggtcacttccttcttcatggagtcctcgcaggtcctctttgacac agagatcttgctggaaaacaaggagtcagtgcacctgggccccttagacactttctgtgaca tcccactcaccatcaaactgcacgtggatgggaaggtgtcgggggtgaaagtctacaccttt gatgagaggatagagattgatgcagcactcctgacttctcagccccacagtcccttgtgctc tggctgcaggcctgtgaggtaccaggttctccgcgatcccccatttgccagtggtttgcccg tggtggtgacacattctcacaggaagttcacggacgtggaggtcacacctggacagatgtat cagtaccaagttctagctgaagctggaggagaactgggagaagcttcgcctcctctgaacca cattcatggagctccttattgtggagatgggaaggtgtcagagagactgggagaagagtgtg atgatggagaccttgtgagcggagatggctgctccaaggtgtgtgagctggaggaaggtttc aactgtgtaggagagccaagcctttgctacatgtatgagggagatggcatatgtgaaccttt tgagagaaaaaccagcattgtagactgtggcatctacactcccaaag gatacttggatcaat gggctacccgggcttactcctctcatgaagacaagaagaagtgtcctgtttccttggtaact ggagaacctcattccctaatttgcacatcataccatccagatttacccaaccaccgtcccct aactggctggtttccctgtgttgccagtgaaaatgaaactcaggatgacaggagtgaacagc cagaaggtagcctgaagaaagaggatgaggtttggctcaaagtgtgtttcaatagaccagga gaggccagagcaatttttatttttttgacaactgatggcctagttcccggagagcatcagca gccgacagtgactctctacctgaccgatgtccgtggaagcaaccactctcttggaacctatg gactgtcatgccagcataatccactgattatcaatgtgacccatcaccagaatgtccttttc caccataccacctcagtgctgccgaatttctcatccccacgggtcggcatctcagctgtggc tctaaggacatcctcccgcattggtctttcggctcccagtaactgcatctcagaggacgagg ggcagaatcatcagggacagagctgtatccatcggccctgtgggaagcaggacagctgtccg tcattgctgcttgatcatgctgatgtggtgaactgtacctctataggcccaggtctcatgaa gtgtgctatcacttgtcaaaggggatttgcccttcaggccagcagtgggcagtacatcaggc ccatgcagaaggaaattctgctcacatgttcttctgggcactgggaccagaatgtgagctgc cttcccgtggactgcggtgttcccgacccgtctttggtgaactatgcaaacttctcctgctc agagggaaccaaatttctgaaacgctgctcaatctcttgtgtcccaccagccaagctgcaag gactgagcccatggctgacatgtcttgaagatggtctctggtctctccctgaagt ctactgc aagttggagtgtgatgctccccctattattctgaatgccaacttgctcctgcctcactgcct ccaggacaaccacgacgtgggcaccatctgcaaatatgaatgcaaaccagggtactatgtgg cagaaagtgcagagggtaaagtcaggaacaagctcctgaagatacaatgcctggaaggtgga atctgggagcaaggcagctgcattcctgtggtgtgtgagccaccccctcctgtgtttgaagg catgtatgaatgtaccaatggcttcagcctggacagccagtgtgtgctcaactgtaaccagg aacgtgaaaagcttcccatcctctgcactaaagagggcctgtggacccaggagtttaagttg tgtgagaatctgcaaggagaatgcccaccacccccctcagagctgaattctgtggagtacaa atgtgaacaaggatatgggattggtgcagtgtgttccccattgtgtgtaatcccccccagtg accccgtgatgctacctgagaatatcactgctgacactctggagcactggatggaacctgtc aaagtccagagcattgtgtgcactggccggcgtcaatggcacccagaccccgtcttagtcca ctgcatccagtcatgtgagcccttccaagcaaatggttggtgtgacactatcaacaaccgag cctactgccactatgacgggggagactgctgctcttccacactctcctccaagaaggtcatt ccatttgctgctgactgtgacctggatgagtgcacctgccgggaccccaaggcagaagaaaa tcagtaactgtgggaacaagcccctccctccactgcctcagaggcagtaagaaagagaggcc gacccaggaggaaacaaagggtgaatgaagaagaacaatcatgaaatggaagaaggaggaag agcatgaaggatcttataagaaatgcaagaggatattgataggtgtg aactagttcatcaag tagcccaagtaggagagaatcataggcaaaagtttctttaaagtggcagttgattaacatgg aaggggaaatatgatagatatataaggaccctccacctgcccgggcggccgctc oder derem komplementären Strang,or its complementary strand, (b) DNA-Sequenzen, die unter stringenten Bedingungen an Proteine kodierende Bereiche einer DNA-Sequenz nach (a) oder an Fragmente einer derartigen DNA-Sequenz hybridisieren,(b) DNA sequences which hybridize under stringent conditions to regions of a DNA sequence according to (a) which code for proteins or to fragments of such a DNA sequence, (c) DNA-Sequenzen, die aufgrund einer Degeneration des genetischen Codes an DNA-Sequenzen nach (a) oder (b) hybridisieren,(c) DNA sequences which hybridize to DNA sequences according to (a) or (b) due to a degeneration of the genetic code, (d) allelen Variationen und Mutationen, die sich durch Sub- stitution, Insertion oder Deletion von einzelnen oder mehreren Nucleotiden oder Inversion von einzelnen oder mehreren Nucleotidteilsequenzen der DNA-Sequenzen nach (a) bis (c) er¬ geben, wobei die Variationen und Mutanten isofunktionelle Ex¬ pressionsprodukte kodieren.to give (d) allelic variations and mutations that stitution by sub- insertion or deletion of single or several nucleotides, or inversion of single or multiple Nucleotidteilsequenzen the DNA sequences of (a) to (c) ¬, said variations and mutants isofunctional ex ¬ pressionsprodukte encode. 2. Rekombinierter Expressionsvektor, der' eine DNA-Sequenz nach Anspruch 1 enthält.2. Recombined expression vector containing 'a DNA sequence according to claim 1. 3. Prokaryotische oder eukaryotische Zelle, die mit einer DNA-Sequenz nach Anspruch 1 oder einem rekombinierten Expressionsvektor nach Anspruch 2 transformiert oder transfiziert ist .3. Prokaryotic or eukaryotic cell, which is transformed or transfected with a DNA sequence according to claim 1 or a recombined expression vector according to claim 2. 4. Expressions- oder Teilexpressionsprodukt einer DNA- Sequenz nach Anspruch 1 oder eines rekombinierten Expres¬ sionsvektors nach Anspruch 2. 4. Expression or partial expression product of a DNA sequence according to claim 1 or a recombined expression ¬ sionsvektor according to claim 2. 5. Verfahren zur Herstellung eines Expressions- oder Teilexpressionsproduktes nach Anspruch 4, bei dem eine Zelle nach Anspruch 3 in einem geeigneten Kulturmedium kultiviert und das Expressions- oder Teilexpressionsprodukt aus den Zel- len und/oder dem Kulturmedium isoliert wird.5. A method for producing an expression or partial expression product according to claim 4, in which a cell according to claim 3 is cultivated in a suitable culture medium and the expression or partial expression product is isolated from the cells and / or the culture medium. 6. Aminosäuresequenz, die eine Aminosäuresequenz umfaßt, welche ausgewählt ist unter6. Amino acid sequence comprising an amino acid sequence which is selected from (a) der folgenden Aminosäuresequenz:(a) the following amino acid sequence: -82 MAATTTTAIFTTLNEPKPETQR -61-82 MAATTTTAIFTTLNEPKPETQR -61 -60 RGWAKSRQRRQVWKRRAEDGQGDSGISSHFQPWPKHSLKHRVKKSPPEESNQNGGEGSYR -1-60 RGWAKSRQRRQVWKRRAEDGQGDSGISSHFQPWPKHSLKHRVKKSPPEESNQNGGEGSYR -1 1 EAETFNSQVGLPILYFSGRRERLLLRPEVLAEIPREAFTVEAWVKPEGGQNNPAIIAGVF 60 61 DNCSHTVSDKGWALGIRSGKDKGKRDARFFFS CTDRVKECATILISHSRYQPGTWTHVAA 1201 EAETFNSQVGLPILYFSGRRERLLLRPEVLAEIPREAFTVEAWVKPEGGQNNPAIIAGVF 60 61 DNCSHTVSDKGWALGIRSGKDKGKRDARFFFS CTDRVKECATILISHSRYQPGTWTHVAA 120 121 TYDGRHMALYVDGTQVASSLDQSGPLNSPFMASCRS LLGGDSSEDGHYFRGHLGTLVFW 180121 TYDGRHMALYVDGTQVASSLDQSGPLNSPFMASCRS LLGGDSSEDGHYFRGHLGTLVFW 180 181 STALPQSHFQHSSQHSSEEEEATDLVLTASFEPVNTEWVPFRDEKYPRLEVLQGFEPEPE 240181 STALPQSHFQHSSQHSSEEEEATDLVLTASFEPVNTEWVPFRDEKYPRLEVLQGFEPEPE 240 241 ILSPLQPP CGQTVCDNVELISQYNGYWPLRGEKVIRYQVVNICDDEGLNPIVSEEQIR 300241 ILSPLQPP CGQTVCDNVELISQYNGYWPLRGEKVIRYQVVNICDDEGLNPIVSEEQIR 300 301 QHEALNEAFSRYNISWQLSVHQVHNSTLRHRVVLVNCEPSKIGNDHCDPECEHPLTGYDG 360 361 GDCRLQGRCYSWNRRDGLCHVECNNMLNDFDDGDCCDPQVADVRKTCFDPDSPKRAYMSV 420301 QHEALNEAFSRYNISWQLSVHQVHNSTLRHRVVLVNCEPSKIGNDHCDPECEHPLTGYDG 360 361 GDCRLQGRCYSWNRRDGLCHVECNNMLNDFDDGDCCDPQVADVRKTCFDPDSPKRAYMSV 420 421 KELKEALQLNSTHFLNIYFASSVREDLAGAATWPWDKDAVTHLGGIVLSPAYYGMPGHTD 480421 KELKEALQLNSTHFLNIYFASSVREDLAGAATWPWDKDAVTHLGGIVLSPAYYGMPGHTD 480 481 TM1HEVGHVLGLYHVFKGVSERESCNDPCKETVPSMETGDLCADTAPTPKSELCREPEPT 540481 TM1HEVGHVLGLYHVFKGVSERESCNDPCKETVPSMETGDLCADTAPTPKSELCREPEPT 540 541 SDTCGFTRFPGAPFTNYMSYTDDNCTDNFTPNQVARMHCYLDLVYQQWTESRKPTPTPIP 600541 SDTCGFTRFPGAPFTNYMSYTDDNCTDNFTPNQVARMHCYLDLVYQQWTESRKPTPTPIP 600 601 PMVIGQTNKSLTIHWLPPISGVVYDRASGSLCGACTEDGTFRQYVHTASSRRVCDSSGY 660 661 TPEEAVGPPDVDQPCEPSLQAWSPEVHLYHMNMTVPCPTEGCSLELLFQHPVQADTLTLW 720601 PMVIGQTNKSLTIHWLPPISGVVYDRASGSLCGACTEDGTFRQYVHTASSRRVCDSSGY 660 661 TPEEAVGPPDVDQPCEPSLQAWSPEVHLYHMNMTVPCPTEGCSLELLFQHPVQADTLTLW 721 VTSFFMESSQVLFDTEI LENKESVHLGPLDTFCDIPLTIKLHVDGKVSGVKVYTFDERI 780721 VTSFFMESSQVLFDTEI LENKESVHLGPLDTFCDIPLTIKLHVDGKVSGVKVYTFDERI 780 781 EIDAALLTSQPHSPLCSGCRPVRYQVLRDPPFASGLPVVVTHSHRKFTDVEVTPGQMYQY 840781 EIDAALLTSQPHSPLCSGCRPVRYQVLRDPPFASGLPVVVTHSHRKFTDVEVTPGQMYQY 840 841 QVLAEAGGELGEASPPLNHIHGAPYCGDGKVSERLGEECDDGDLVSGDGCSKVCELEEGF 900841 QVLAEAGGELGEASPPLNHIHGAPYCGDGKVSERLGEECDDGDLVSGDGCSKVCELEEGF 900 901 NCVGEPSLCYMYEGDGICEPFERKTSIVDCGIYTPKGYLDQWATRAYSSHEDKKKCPVSL 960 961 VTGEPHSLICTSYHPDLPNHRPLTGWFPCVASENETQDDRSEQPEGSLKKEDEVWLKVCF 1020901 NCVGEPSLCYMYEGDGICEPFERKTSIVDCGIYTPKGYLDQWATRAYSSHEDKKKCPVSL 960 961 VTGEPHSLICTSYHPDLPNHRPLTGWFPCVASENETQDDRSEQPEGSLKKEDEVWLKVCF 1020 1021 NRPGEARAIFIFLTTDGLVPGEHQQPTVTLYLTDVRGSNHSLGTYGLSCQHNPLIINVTH 10801021 NRPGEARAIFIFLTTDGLVPGEHQQPTVTLYLTDVRGSNHSLGTYGLSCQHNPLIINVTH 1080 1081 HQNVLFHHTTSVLPNFSSPRVGISAVALRTSSR1GLSAPSNCISEDEGQNHQGQSCIHRP 11401081 HQNVLFHHTTSVLPNFSSPRVGISAVALRTSSR1GLSAPSNCISEDEGQNHQGQSCIHRP 1140 1141 CG QDSCPSLLLDHADVVNCTSIGPGLMKCAITCQRGFALQASSGQYIRPMQKEILLTCS 12001141 CG QDSCPSLLLDHADVVNCTSIGPGLMKCAITCQRGFALQASSGQYIRPMQKEILLTCS 1200 1201 SGH DQNVSCLPVDCGVPDPSLVNYANFSCSEGTKFLKRCS1SCVPPAKLQG SPWLTCL 1260 1261 EDG SLPEVYCKLECDAPPIILNANLLLPHCLQDNHDVGTICKYECKPGYYVAESAEGK 13201201 SGH DQNVSCLPVDCGVPDPSLVNYANFSCSEGTKFLKRCS1SCVPPAKLQG SPWLTCL 1260 1261 EDG SLPEVYCKLECDAPPIILNANLLLPHCLQDNHDVGTICKYECKPGYYVAESAEGK 1320 1321 VRNKLLKIQCLEGGIWEQGSCIPVVCEPPPPVFEGMYECTNGFSLDSQCVLNCNQEREKL 13801321 VRNKLLKIQCLEGGIWEQGSCIPVVCEPPPPVFEGMYECTNGFSLDSQCVLNCNQEREKL 1380 1381 PILCTKEGL TQEFKLCENLQGECPPPPSELNSVEYKCEQGYGIGAVCSPLCVIPPSDPV 14401381 PILCTKEGL TQEFKLCENLQGECPPPPSELNSVEYKCEQGYGIGAVCSPLCVIPPSDPV 1440 1441 MLPENITADTLEHWMEPVKVQSIVCTGRRQWHPDPVLVHCIQSCEPFQANG CDTINNRA 15001441 MLPENITADTLEHWMEPVKVQSIVCTGRRQWHPDPVLVHCIQSCEPFQANG CDTINNRA 1500 1501 YCHYDGGDCCSSTLSSKKVIPFAADCDLDECTCRDPKAEENQ1501 YCHYDGGDCCSSTLSSKKVIPFAADCDLDECTCRDPKAEENQ (b) einer Aminosäuresequenz, bei der es sich um eine allele isofunktionelle Variante der in (a) definierten Aminosäuresequenz handelt, (c) einer Mutante der in (a) oder (b) definierten Aminosäuresequenz, bei der ein oder mehrere Aminosäurerest (e) deletiert und/oder ersetzt und/oder insertiert und/oder eine oder mehrere Aminosäureteilsequenz (en) invertiert ist/sind und welche isofunktionell ist,(b) an amino acid sequence which is an allelic isofunctional variant of the amino acid sequence defined in (a), (c) a mutant of the amino acid sequence defined in (a) or (b), in which one or more amino acid residues (e) are deleted and / or replaced and / or inserted and / or one or more amino acid partial sequence (s) is / are inverted and which is isofunctional, (d) einer Aminosäuresequenz, an deren C-Terminus und/oder N- Terminus eine Aminosäuresequenz fusioniert ist, wobei das sich ergebende Fusionsprotein isofunktionell ist und/oder die zusätzlichen C-terminalen oder N-terminalen Aminosäuresequenzen leicht abgespalten werden können.(d) an amino acid sequence at whose C-terminus and / or N-terminus an amino acid sequence is fused, the resulting fusion protein being isofunctional and / or the additional C-terminal or N-terminal amino acid sequences can be easily cleaved off. 7. Polyklonaler oder monoklonaler Antikörper, der gegen ein Expressionsprodukt oder eine Aminosäuresequenz nach einem der' vorherigen Ansprüche gerichtet ist.7. Polyclonal or monoclonal antibody which is directed against an expression product or an amino acid sequence according to one of the ' preceding claims. 8. Verwendung einer DNA-Sequenz oder eines Expressionsproduktes oder einer Aminosäuresequenz oder eines Antikörpers nach einem der vorherigen Ansprüche in einem Assay zur human- genetischen Diagnostik.8. Use of a DNA sequence or an expression product or an amino acid sequence or an antibody according to any one of the preceding claims in an assay for human genetic diagnostics. 9. Verwendung nach Anspruch 8, wobei der Assay zum Nachweis von Trisomie 13, 18, 21 oder 22 dient.9. Use according to claim 8, wherein the assay is used to detect trisomy 13, 18, 21 or 22. 10. Kit zur Verwendung in einem Assay zur humangenetischen Diagnostik, der eine DNA-Sequenz oder ein Expressionsprodukt oder eine Aminosäuresequenz oder einen Antikörper nach einem der vorherigen Ansprüche enthält. 10. Kit for use in an assay for human genetic diagnosis, which contains a DNA sequence or an expression product or an amino acid sequence or an antibody according to any one of the preceding claims. 11. Kit nach Anspruch 10, wobei der Assay zum Nachweis von Trisomie 13, 18, 21 oder 22 dient.11. The kit of claim 10, wherein the assay serves to detect trisomy 13, 18, 21 or 22. 12. Verwendung einer DNA-Sequenz oder eines Expressionsproduktes oder einer Aminosäuresequenz nach einem der vorherigen Ansprüche in einem Assay zum Auffinden von Antagonisten gegen PAPP-E. 12. Use of a DNA sequence or an expression product or an amino acid sequence according to one of the preceding claims in an assay for finding antagonists against PAPP-E.
PCT/EP2001/006831 2000-06-16 2001-06-15 Pregnancy-associated plasma protein-e (papp-e) Ceased WO2001095855A2 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032953A3 (en) * 2000-10-20 2003-01-09 Como Biotech Aps Pregnancy-associated plasma protein-a2 (papp-a2)
WO2011144999A1 (en) * 2010-05-17 2011-11-24 Sandra Reznik Plasma protein-a2 (papp-a2) as a marker for detecting risk of chromosomal abnormalities

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002032953A3 (en) * 2000-10-20 2003-01-09 Como Biotech Aps Pregnancy-associated plasma protein-a2 (papp-a2)
US7083940B2 (en) 2000-10-20 2006-08-01 Como Biotech Aps Pregnancy-associated plasma protein-A2 (PAPP-A2)
US20130095482A1 (en) * 2000-10-20 2013-04-18 Claus Oxvig Methods of detecting pregnancy-associated plasma protein-a2 (papp-a2)
US9005949B2 (en) 2000-10-20 2015-04-14 Como Biotech Aps Pregnancy-associated plasma protein-A2 (PAPP-A2) polynucleotides
WO2011144999A1 (en) * 2010-05-17 2011-11-24 Sandra Reznik Plasma protein-a2 (papp-a2) as a marker for detecting risk of chromosomal abnormalities

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