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WO1998059050A9 - Clonage d'une mutation genique permettant de deceler la maladie de parkinson - Google Patents

Clonage d'une mutation genique permettant de deceler la maladie de parkinson

Info

Publication number
WO1998059050A9
WO1998059050A9 PCT/US1998/013071 US9813071W WO9859050A9 WO 1998059050 A9 WO1998059050 A9 WO 1998059050A9 US 9813071 W US9813071 W US 9813071W WO 9859050 A9 WO9859050 A9 WO 9859050A9
Authority
WO
WIPO (PCT)
Prior art keywords
mutation
synuclein
nucleic acid
protein
disease
Prior art date
Application number
PCT/US1998/013071
Other languages
English (en)
Other versions
WO1998059050A1 (fr
Inventor
Mihael H Polymeropoulos
Christian Lavedan
Elisabeth Leroy
Robert L Nussbaum
William G Johnson
Roger C Duvoisin
Original Assignee
Us Health
Mihael H Polymeropoulos
Christian Lavedan
Elisabeth Leroy
Robert L Nussbaum
William G Johnson
Roger C Duvoisin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Us Health, Mihael H Polymeropoulos, Christian Lavedan, Elisabeth Leroy, Robert L Nussbaum, William G Johnson, Roger C Duvoisin filed Critical Us Health
Priority to AU81637/98A priority Critical patent/AU8163798A/en
Priority to US09/446,628 priority patent/US7001720B1/en
Publication of WO1998059050A1 publication Critical patent/WO1998059050A1/fr
Publication of WO1998059050A9 publication Critical patent/WO1998059050A9/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • amino acid 53 may be part of the NAC peptide found in plaques.
  • crosslinking experiments with beta amyloid (Abeta) it was demonstrated (6) that residues 1-56 and 57-97 specifically bind amyloid and that a synthetic peptide consisting of residues 32-57 performed similarly.
  • phenotype could be explained by a combination of factors, including the following: the relative short life span of rodents may prohibit the observation of a late onset disorder, interaction with other cellular components not present in the rat may be required for the phenotype, absence of a critical environmental trigger in the rodents, or finally a heterozygous status Ala/Thr may be necessary for the production of a phenotype.
  • the present invention also includes oligonucleotides complementary to a portion of the synuclein gene, wherein said portion comprises or flanks a mutation associated with predisposition to Parkinson's Disease.
  • the oligonucleotides of the present invention will have a sequence that is complementary to a sequence from the alpha synuclein gene that includes or flanks base pair position 209. And in particular, this mutation is a change from guanine to adenine at this position.
  • the detecting step of the method of the present invention comprises detecting the presence or absence of a restriction endonuclease site as detected by enzymatic digest of a nucleic acid sample.
  • a detecting means will be possible when a mutation associated with a predisposition to Parkinson's disease results in a sequence having a new restriction endonuclease cleavage site, or loss of a native restriction endonuclease site.
  • the mutation associated with Parkinson's disease results in the formation of a non-native Tsp45I restriction endonuclease site.
  • DNA sequence of the PCR product used for mutation detection (SEQ ID NO 1) .
  • Oligonucleotide primers are shown by arrows and the numerals 3 and 13 (SEQ ID NO 2 and 3) .
  • Intron sequence is shown lower case and exon sequence m upper case.
  • Ammo acid translation of the exon is shown below the DNA sequence.
  • the circled base represents the G209A change in the mutant allele.
  • the resulting ammo acid Ala53Thr change is represented by the circled amino acid.
  • the newly created Tsp45 I site is indicated above the DNA sequence .
  • ligase chain reaction may involve the use of mismatch probes, i.e., probes which are fully complementary with the target except at the point of the mutation.
  • the target sequence is then allowed to hybridize both with oligonucleotides which are fully complementary and have oligonucleotides containing a mismatch, under conditions which will distinguish between the two.
  • mismatch probes i.e., probes which are fully complementary with the target except at the point of the mutation.
  • the target sequence is then allowed to hybridize both with oligonucleotides which are fully complementary and have oligonucleotides containing a mismatch, under conditions which will distinguish between the two.
  • the oligonucleotides oriented with their 3' ends pointing towards each other, hybridize to opposite strands of the target sequence and prime enzymatic extension along the nucleic acid template in the presence of the four deoxyribonucleotide triphosphates .
  • the end product is then denatured again for another cycle. After this three-step cycle has been repeated several times, amplification of a DNA segment by more than one million-fold can be achieved.
  • the resulting DNA may then be directly sequenced in order to locate any genetic alteration. Alternatively, it may be possible to prepare oligonucleotides that will only bind to altered DNA, so that PCR will only result in multiplication of the DNA if the mutation is present.
  • PCR may be followed by restriction endonuclease digestion with subsequent analysis of the resultant products .
  • substitution of G for A at base pair 209 of the synuclein results in the gain of a Tsp45I site. The gain of this restriction endonuclease
  • E. coli is one prokaryotic host that is particularly useful for cloning and expression of the DNA sequences of the present invention because of the wide variety of available expression systems.
  • Vectors suitable for use in E. coli are known and are commercially available, i.e. pBR322 (13), pBLUESCRIPT (Stratagene) , etc.
  • pBR322 13
  • pBLUESCRIPT pBLUESCRIPT
  • a variety of different types of expression systems may be used, including plasmids, cosmids, bacteriophage lambda, etc.
  • Other microbial hosts suitable for use include bacilli, such as Bacillus subtilus, and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species.
  • chromosomal region 45
  • pathogenesis of diseases affecting the nigrostriatal pathway includes environmental influences, then a range of mutations affecting vulnerable sites in the electron transport chain or enzyme polymorphisms influencing neurotoxin metabolism may vary the penetrance of PD by altering an individual ' s resistance to exogenous or endogenous agents.
  • our finding of a highly penetrant genetic locus linked to PD suggested that abnormalities of a single gene may be sufficient to cause Parkinson's disease.
  • Parkinson's disease we conducted sequence analysis of candidate genes in this region.
  • ORGANISM Serinus canaria
  • C INDIVIDUAL ISOLATE: genbank L33860
  • GGGCATNTGC GTCCCGCGGG AGGGGCTGGG GTGAGAGTGC GGGGCCAGTG CACCGGTGCC
  • GAAGACCAAG GAGGGCGTCC TCTACGTCGG TGGGCNGGGG GCNGGGTTTC TGGGGCTGCA
  • ANCCCATAGA ANCCTGGGTC TGTATCCGGA AATGGGGACA CGGGGCGGGC TGATGAGGTG GGGGGCTCCA NCTGAAAGGC CAGGGACCAN TGCANTNATA AAANCACACA NCCTCCTTTT
  • OLECULAR TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • IMMEDIATE SOURCE
  • A LENGTH: 650 base pairs
  • B TYPE: NUCLEIC ACID
  • C STRANDEDNESS :DOUBLE
  • D TOPOLOGY: LINEAR
  • MOLECULAR TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • IMMEDIATE SOURCE (A) CLONE: human alpha synuclein gene/ exon 4 plus flanking intron sequences
  • CTGCAGGTCA ACGGATCTGT CTCTAGTGCT GTACTTTTAA AGCTTCTACA GTTCTGAATT CAAAATTATC TTCTCACTGG GCCCCGGTGT TATCTCATTC TTTTTTCTCC TCTGTAAGTT GACATGTGAT GTGGGAACAA AGGGGATAAA GTCATTATTT TGTGCTAAAA TCGTAATTGG AGAGGACCTC CTGTTAGCTG GGCTTTCTTC TATNTATTGT GGTGGTTAGG AGTTCCTTCT TCTAGTTTTA GGATATATAT ATATATTTTT TCTTTCCCTG AAGATATAAT AATATATATA CTTCTGAAGA TTGAGATTTT TAAATTAGTT GTATTGAAAA CTAGCTAATC AGCAATTTAA GGCTAGCTTG AGACTTATGT CTTGAATTTG TTTTTGTAGG CTCCAAAACC AAGGAGGGAG TGGTGCATGG TGTGGCAACA GGTAAGCTCC ATTGTGCTTA TATCAAAGAT GATATNTA
  • A LENGTH: 727 base pairs
  • B TYPE: NUCLEIC ACID
  • C STRANDEDNESS :DOUBLE
  • D TOPOLOGY: LINEAR
  • MOLECULAR TYPE DNA (genomic)
  • HYPOTHETICAL NO
  • ANTI-SENSE NO
  • IMMEDIATE SOURCE A) CLONE: human alpha synuclein gene/ exons 1 and 2 plus flanking intron sequences
  • POSITION IN GENOME A
  • AAAAGTTTAC ATACTTTGAG GTTGATAACC CATGTTGCCG CAATGTTTCC CCGGAGGCAT TGTGGAGTTT AGAATGCCAG TAGTAATATT AAGGTGTGCC ATTTTCAAGA TCCGTGGCCA ACATCCCTAT ATGTAAGATT TTTCCAAAAC ATGGTTCTGA TTTTTAAAAG TGAAAAATGC TACTTCATCA TGTTCTTTTT GTGCTTCTTA CTTTAAATAT TAGAATGAAG AAGGAGCCCC ACAGGAAGGA ATTCTGGAAG ATATGCCTGT GGATCCTGAC AATGAGGCTT ATGAAATGCC TTCTGAGGTA GGAGTCCAAG CTGAATCTTT CTAACAAGAC AGTACCAAAA ACCTGTCATT GTCACATTTC TCTTTCATTA GTGCTTAGTG AGAATCATTT GCTCTCTACA TGCTCATTA GTGGACAACT TGCAAGTTAA GAATAGTTTTTT TACATTTTTA AAGGGTCCTT AAAAAAAAAG

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La maladie de Parkinson est un trouble neurodégénératif commun ayant une incidence sur la durée de vie d'environ 2 pour cent. Récemment, il a été découvert qu'un gène de susceptibilité de la maladie de Parkinson se situe sur le bras long du chromosome humain 4. La présente invention concerne l'identification ultérieure d'une mutation dans le gène de synucléine alpha, qui code une protéine présynaptique, censée être impliquée dans la plasticité neuronale. La découverte d'une modification moléculaire spécifique responsable de la maladie de Parkinson permettra une compréhension détaillée de la physiopathologie du trouble qui rendra possibles des interventions thérapeutiques potentielles, ainsi que l'obtention de moyens permettant de diagnostiquer des individus présentant un risque accru de développer cette maladie.
PCT/US1998/013071 1997-06-25 1998-06-25 Clonage d'une mutation genique permettant de deceler la maladie de parkinson WO1998059050A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU81637/98A AU8163798A (en) 1997-06-25 1998-06-25 Cloning of a gene mutation for parkinson's disease
US09/446,628 US7001720B1 (en) 1997-06-25 1998-06-25 Cloning of a gene mutation for parkinson's disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5068497P 1997-06-25 1997-06-25
US60/050,684 1997-06-25

Publications (2)

Publication Number Publication Date
WO1998059050A1 WO1998059050A1 (fr) 1998-12-30
WO1998059050A9 true WO1998059050A9 (fr) 1999-04-15

Family

ID=21966755

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/013071 WO1998059050A1 (fr) 1997-06-25 1998-06-25 Clonage d'une mutation genique permettant de deceler la maladie de parkinson

Country Status (2)

Country Link
AU (1) AU8163798A (fr)
WO (1) WO1998059050A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9719879D0 (en) * 1997-09-19 1997-11-19 Neuropa Ltd Protein
WO1999050300A1 (fr) * 1998-03-30 1999-10-07 The Trustees Of The University Of Pennsylvania Methode d'identification, de diagnostic et de traitement de troubles neurodegeneratifs a niveaux eleves de synucleine
EP1081225A1 (fr) * 1999-08-30 2001-03-07 Biofrontera Pharmaceuticals GmbH Modèle animal transgénique de maladies neurodégénératives
AU2001260140A1 (en) 2000-03-22 2001-10-03 Avntis Pharma Deutschland Gmbh Nematodes as model organisms for the investigation of neurodegenerative diseases, in particular parkinsons disease, uses and methods for the discovery of substances and genes which can be used in the treatment of the above disease states and identification of a nematode gene.
EP1299411A4 (fr) * 2000-07-07 2006-02-15 Panacea Pharm Llc Procedes pour la prevention des degats relatifs aux tissus nerveux et pour le traitement des maladies liees a l'alpha-synucleine
US20040146935A1 (en) * 2001-03-15 2004-07-29 Roberts Rosalinda Cusido Disease associated gene
US8506959B2 (en) 2002-11-01 2013-08-13 Neotope Biosciences Limited Prevention and treatment of synucleinopathic and amyloidogenic disease
TW200509968A (en) 2002-11-01 2005-03-16 Elan Pharm Inc Prevention and treatment of synucleinopathic disease
US7550649B2 (en) 2003-10-30 2009-06-23 Taisho Pharmaceutical Co., Ltd. Transgenic non-human mammal
MX2007001679A (es) 2004-08-09 2007-05-23 Elan Pharm Inc Prevencion y tratamiento de la enfermedad sinucleinopatica y amiloidogenica.
SI3067066T1 (sl) 2007-02-23 2019-08-30 Prothena Biosciences Limited Preventiva in zdravljenje sinukleinopatske in amiloidogene bolezni
CA2678963C (fr) 2007-02-23 2018-05-01 Elan Pharmaceuticals, Inc. Prevention et traitement de maladies synucleinopathiques et amyloidogeniques

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494794A (en) * 1992-10-20 1996-02-27 Emory University Detection of mitochondrial DNA mutations associated with Alzheimer's disease and Parkinson's disease

Also Published As

Publication number Publication date
WO1998059050A1 (fr) 1998-12-30
AU8163798A (en) 1999-01-04

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