Document Detail

Mutation detection in Machado-Joseph disease using repeat expansion detection.
MedLine Citation:
PMID:  8900536     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Several neurological disorders have recently been explained through the discovery of expanded DNA repeat sequences. Among these is Machado-Joseph disease, one of the most common spinocerebellar ataxias (MJD/SCA3), caused by a CAG repeat expansion on chromosome 14. A useful way of detecting repeat sequence mutations is offered by the repeat expansion detection method (RED), in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA. We have used RED to detect CAG expansions in families with either MJD/SCA3 or with previously uncharacterized spinocerebellar ataxia (SCA). MATERIALS AND METHODS: Five MJD/SCA3 families and one SCA family where linkage to SCA1-5 had been excluded were analyzed by RED and polymerase chain reaction (PCR). RESULTS: An expansion represented by RED products of 180-270 bp segregated with MJD/SCA3 (p < 0.00001) in five families (n = 60) and PCR products corresponding to 66-80 repeat copies were observed in all affected individuals. We also detected a 210-bp RED product segregating with disease (p < 0.01) in a non-SCA1-5 family (n = 16), suggesting involvement of a CAG expansion in the pathophysiology. PCR analysis subsequently revealed an elongated MJD/SCA3 allele in all affected family members. CONCLUSIONS: RED products detected in Machado-Joseph disease families correlated with elongated PCR products at the MJD/SCA3 locus. We demonstrate the added usefulness of RED in detecting repeat expansions in disorders where linkage is complicated by phenotyping problems in gradually developing adult-onset disorders, as in the non-SCA1-5 family examined. The RED method is informative without any knowledge of flanking sequences. This is particularly useful when studying diseases where the mutated gene is unknown. We conclude that RED is a reliable method for analyzing expanded repeat sequences in the genome.
K Lindblad; A Lunkes; P Maciel; G Stevanin; C Zander; T Klockgether; T Ratzlaff; A Brice; G A Rouleau; T Hudson; G Auburger; M Schalling
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular medicine (Cambridge, Mass.)     Volume:  2     ISSN:  1076-1551     ISO Abbreviation:  Mol. Med.     Publication Date:  1996 Jan 
Date Detail:
Created Date:  1997-01-02     Completed Date:  1997-01-02     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  9501023     Medline TA:  Mol Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  77-85     Citation Subset:  IM    
Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden. KELI@GEN.KS.SE
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MeSH Terms
Base Sequence
DNA Primers / chemistry
Electrophoresis, Polyacrylamide Gel
Linkage (Genetics) / genetics
Machado-Joseph Disease / genetics*
Molecular Sequence Data
Mutation / genetics
Polymerase Chain Reaction
Repetitive Sequences, Nucleic Acid / genetics*
Reg. No./Substance:
0/DNA Primers

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