CA2248016A1 - Direct molecular diagnosis of friedreich ataxia - Google Patents

Direct molecular diagnosis of friedreich ataxia

Info

Publication number
CA2248016A1
CA2248016A1 CA002248016A CA2248016A CA2248016A1 CA 2248016 A1 CA2248016 A1 CA 2248016A1 CA 002248016 A CA002248016 A CA 002248016A CA 2248016 A CA2248016 A CA 2248016A CA 2248016 A1 CA2248016 A1 CA 2248016A1
Authority
CA
Canada
Prior art keywords
seq
molecule
matter
composition
gene
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
CA002248016A
Other languages
French (fr)
Other versions
CA2248016C (en
Inventor
Massimo Pandolfo
Laura Montermini
Maria Molto
Michael Koenig
Victoria Campuzano
Mireille Cossee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut National de la Sante et de la Recherche Medicale INSERM
Baylor College of Medicine
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of CA2248016A1 publication Critical patent/CA2248016A1/en
Application granted granted Critical
Publication of CA2248016C publication Critical patent/CA2248016C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C12Q2600/158—Expression markers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/81—Packaged device or kit

Abstract

The invention relates generally to methods for the diagnosis and therapeutic treatment of Friedreich Ataxia. Friedreich ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous system and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. The gene encodes a 210 amino acid protein, frataxin, that has homologues in distant species such as C.
elegans and yeast. A few FRDA patients have been found to have point mutations in X25, but the vast majority are homozygous for a variable, unstable GAA
trinucleotide expansion in the first X25 intron. Mature X25 mRNA was severely reduced in abundance in individuals with FRDA. Carriers and individuals at risk for developing FRDA can be ascertained by the methods of the present invention. Further, the methods of the present invention provide treatment to those individuals having FRDA.

Claims (52)

1. A method of screening individuals for a mutation that leads to Friedreich's ataxia, comprising the steps of digesting DNA from an individual to be tested with a restriction endonuclease: and measuring the length of a restriction fragment length polymorphism (RFLP) by hybridization to probes that recognize a region encompassing a GAA repeat in the first intron of an X25 gene and performing Southern Blot analysis, wherein an RFLP having said GM
expansion of more than about 120 is an indication of said mutation that leads to Friedreich's ataxia.
2. The method of claim 1, wherein the restriction endonuclease is EcoRI.
3. The method of claim 1, wherein the probe used for performing said Southern Blot is SEQ ID NO 2.
4. The method of claim 1, wherein the probe used for performing said Southern Blot is an amplification product obtained by performing PCR on said DNA with SEQ ID NO 16 and SEQ ID NO 17.
5. A method of screening individuals for a mutation that leads to Friedreich's ataxia, comprising the steps of measuring expression of an X25 gene by determining an amount of mRNA expressed from said X25 gene and from known controls, and comparing the amount of mRNA from said X25 gene to the amount of mRNA from the known controls.
6. The method of claim 5 wherein the mRNA is determined by the steps of:
extracting mRNA from individuals to be tested;
preparing cDNA from mRNA;
amplifying said cDNA to produce amplification products; and comparing relative amounts of X25 and control amplification products present, wherein a reduced amount of mRNA from the X25 gene indicates individuals having said mutation that leads to Friedreich's ataxia.
7. The method of claim 6, wherein the comparing step includes electrophoresis of said amplification products; transfering said amplification products to a solid support; hybridizing said amplification products to a probe: and quantifying of X25 amplification products versus control gene amplification products.
8. The method of claim 6, wherein said probe is SEQ ID NO 14.
9. The method of claim 5, wherein said control gene is serine hydroxymethyltransferase (SHMT).
10. A method of screening individuals for a mutation that leads to Friedreich's ataxia. comprising the step of detecting a variation in a size of a (GAA)n repeat in a first intron of a X25 gene by measuring a length of said repeat, wherein n for normal individuals ranges from 1-22 and n for affected individuals is 120.
11. The method of claim 10, wherein said size of said repeat is measured by restriction endonuclease digestion of sample DNA and Southern Blot analysis.
12. The method of claim 10. wherein said size of said repeat is determined by pulsed field gel electrophoresis.
13. The method of claim 10 wherein SEQ ID NO 29 and SEQ ID NO 30 are used in said detecting step.
14. The method of claim 10, wherein SEQ ID NO 31 and SEQ ID NO 32 are used in said detecting steps.
15. A method for detecting a GAA polymorphism in a first intron of an X25 gene comprising the steps of performing a PCR assay to produce amplified products of said first intron of said X25 gene and measuring the length of said amplified products.
16. The method of claim 15, wherein SEQ ID NO 29 and SEQ ID NO 30 are used in said PCR assay.
17. The method of claim 15. wherein SEQ ID NO 31 and SEQ ID NO 32 are used in said PCR assay.
18. A method of screening individuals for a mutation that leads to Friedreich's ataxia, comprising the steps of sequencing DNA from an individual, and comparing said sequence from said individual to SEQ ID
NOS 1-12 to determine what differences there are between said sequence from said individual and SEQ ID NOS 1-12.
19. A method of treating Friedreich's ataxia, comprising the step of administering a pharmacologic dose of a protein having an amino acid sequence substantially similar to SEQ ID NO 4 to an individual.
20. A method of treating Friedreich's ataxia, comprising administration to an individual of a nucleic acid vector containing an X25 gene capable of expression.
21. As a composition of matter, the molecule having SEQ ID NO 1.
22. As a composition of matter, the molecule having SEQ ID NO 2.
23. As a composition of matter, the molecule having SEQ ID NO 3.
24. As a composition of matter, the molecule having SEQ ID NO 4.
25. As a composition of matter, the molecule having SEQ ID NO 5.
26. As a composition of matter, the molecule having SEQ ID NO 6.
27. As a composition of matter, the molecule having SEQ ID NO 7.
28. As a composition of matter, the molecule having SEQ ID NO 8.
29. As a composition of matter, the molecule having SEQ ID NO 9.
30. As a composition of matter, the molecule having SEQ ID NO 10.
31. As a composition of matter, the molecule having SEQ ID NO 11.
32. As a composition of matter, the molecule having SEQ ID NO 12.
33. As a composition of matter, the molecule having SEQ ID NO 13.
34. As a composition of matter, the molecule having SEQ ID NO 14.
35. As a composition of matter, the molecule having SEQ ID NO 15.
36. As a composition of matter, the molecule having SEQ ID NO 16.
37. As a composition of matter, the molecule having SEQ ID NO 17.
38. As a composition of matter, the molecule having SEQ ID NO 18.
39. As a composition of matter, the molecule having SEQ ID NO 19.
40. As a composition of matter, the molecule having SEQ ID NO 20.
41. As a composition of matter, the molecule having SEQ ID NO 21.
42. As a composition of matter, the molecule having SEQ ID NO 22.
43. As a composition of matter, the molecule having SEQ ID NO 23.
44. As a composition of matter, the molecule having SEQ ID NO 24.
45. As a composition of matter, the molecule having SEQ ID NO 25.
46. As a composition of matter, the molecule having SEQ ID NO 26.
47. As a composition of matter, the molecule having SEQ ID NO 27.
48. As a composition of matter, the molecule having SEQ ID NO 28.
49. As a composition of matter, the molecule having SEQ ID NO 29.
50. As a composition of matter, the molecule having SEQ ID NO 30.
51. As a composition of matter, the molecule having SEQ ID NO 31.
52. As a composition of matter, the molecule having SEQ ID NO 32.
CA2248016A 1996-03-06 1997-03-04 Direct molecular diagnosis of friedreich ataxia Expired - Lifetime CA2248016C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/611,587 1996-03-06
US08/611,587 US6150091A (en) 1996-03-06 1996-03-06 Direct molecular diagnosis of Friedreich ataxia
PCT/EP1997/001070 WO1997032996A1 (en) 1996-03-06 1997-03-04 Direct molecular diagnosis of friedreich ataxia

Publications (2)

Publication Number Publication Date
CA2248016A1 true CA2248016A1 (en) 1997-09-12
CA2248016C CA2248016C (en) 2011-05-10

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
CA2248016A Expired - Lifetime CA2248016C (en) 1996-03-06 1997-03-04 Direct molecular diagnosis of friedreich ataxia

Country Status (8)

Country Link
US (1) US6150091A (en)
EP (1) EP0885309B1 (en)
JP (1) JP4602481B2 (en)
AT (1) ATE265544T1 (en)
AU (1) AU2095097A (en)
CA (1) CA2248016C (en)
DE (1) DE69728864T2 (en)
WO (1) WO1997032996A1 (en)

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JP2010154858A (en) * 1996-03-06 2010-07-15 Inst National De La Sante & De La Recherche Medicale Direct molecular diagnosis of friedreich ataxia
EP0972025A1 (en) 1997-01-21 2000-01-19 Human Genome Sciences, Inc. I-flice, a novel inhibitor of tumor necrosis factor receptor-1 and cd-95 induced apoptosis
US6710226B1 (en) 1997-12-02 2004-03-23 Neuralab Limited Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics
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US7179892B2 (en) 2000-12-06 2007-02-20 Neuralab Limited Humanized antibodies that recognize beta amyloid peptide
US20080050367A1 (en) 1998-04-07 2008-02-28 Guriq Basi Humanized antibodies that recognize beta amyloid peptide
US6750324B1 (en) 1997-12-02 2004-06-15 Neuralab Limited Humanized and chimeric N-terminal amyloid beta-antibodies
US6743427B1 (en) 1997-12-02 2004-06-01 Neuralab Limited Prevention and treatment of amyloidogenic disease
US7790856B2 (en) 1998-04-07 2010-09-07 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US6913745B1 (en) 1997-12-02 2005-07-05 Neuralab Limited Passive immunization of Alzheimer's disease
US6923964B1 (en) 1997-12-02 2005-08-02 Neuralab Limited Active immunization of AScr for prion disorders
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US6761888B1 (en) * 2000-05-26 2004-07-13 Neuralab Limited Passive immunization treatment of Alzheimer's disease
DE19820201A1 (en) * 1998-05-06 1999-11-11 Wilhelm Krone Diagnostic test for cardiovascular risk factors and their complications
US20030147882A1 (en) * 1998-05-21 2003-08-07 Alan Solomon Methods for amyloid removal using anti-amyloid antibodies
US6787637B1 (en) 1999-05-28 2004-09-07 Neuralab Limited N-Terminal amyloid-β antibodies
UA81216C2 (en) * 1999-06-01 2007-12-25 Prevention and treatment of amyloid disease
AU1222501A (en) * 1999-10-20 2001-04-30 Hopital Sainte-Justine Identification of arsacs mutations and methods of use therefor
US6812333B1 (en) 1999-10-20 2004-11-02 Hopital Sainte-Justine Identification of arsacs mutations and methods of use therefor
US7700751B2 (en) 2000-12-06 2010-04-20 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize β-amyloid peptide
TWI255272B (en) 2000-12-06 2006-05-21 Guriq Basi Humanized antibodies that recognize beta amyloid peptide
MY139983A (en) 2002-03-12 2009-11-30 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
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PE20061329A1 (en) 2004-12-15 2006-12-08 Neuralab Ltd HUMANIZED AB ANTIBODIES TO IMPROVE COGNITION
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WO2008085898A2 (en) * 2007-01-04 2008-07-17 President And Fellows Of Harvard College Methods for identifying essential proteins and therapeutic agents
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US9476043B2 (en) 2011-04-08 2016-10-25 Rula Zain-Luqman Diagnosis and treatment of friedreich's ataxia
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Also Published As

Publication number Publication date
EP0885309A1 (en) 1998-12-23
AU2095097A (en) 1997-09-22
DE69728864D1 (en) 2004-06-03
DE69728864T2 (en) 2005-07-28
CA2248016C (en) 2011-05-10
WO1997032996A1 (en) 1997-09-12
ATE265544T1 (en) 2004-05-15
JP4602481B2 (en) 2010-12-22
EP0885309B1 (en) 2004-04-28
US6150091A (en) 2000-11-21
JP2000507093A (en) 2000-06-13

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