Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease
Identifieur interne : 000332 ( France/Analysis ); précédent : 000331; suivant : 000333Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease
Auteurs : Y. Takiyama [Japon] ; S. Igasrashi [Japon] ; E. A. Rogaeva ; K. Endo [Japon] ; E. I. Rogaev ; H. Tanaka [Japon] ; R. Sherrington ; K. Sanpei [Japon] ; Y. Liang ; M. Saito [Japon] ; T. Tsuda ; H. Takano [Japon] ; M. Ikeda ; C. Lin ; H. Chi ; J. L. Kennedy [Canada] ; A. E. Lang [Canada] ; J. R. Wherrett [Canada] ; M. Segawa ; Y. Nomura ; T. Yuasa [Japon] ; J. Weissenbach [France] ; M. Yoshida ; M. Nishizawa ; K. K. Kidd [États-Unis] ; S. Tsuji [Japon] ; P. H. St George-Hyslop [Canada]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 1995-07.
Abstract
The size of the (CAG)n repeat array in the 3′ end of the MJDI gene and the haplotype at a series of microsateilite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD). Our data provide five novel observations. First, MJD is associated with expansion of the array from the normal range of 14–37 repeats to 68–84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups. Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meloses, and this instability was associated with the clinical phenomenon of anticipation. Third, the size of the expanded allele is not only Inversely correlated with the age-of-onset of MJD (r=−0.738, p<0.001), but is also correlated with the frequency of other clinical features [e.g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with larger repeats (p<0.001 and p>0.05 respectively)]. Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD. Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.
Url:
DOI: 10.1093/hmg/4.7.1137
Affiliations:
- Canada, France, Japon, États-Unis
- Connecticut, Ontario, Île-de-France
- Paris, Tokyo, Toronto
- Université de Toronto
Links toward previous steps (curation, corpus...)
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- to stream Istex, to step Checkpoint: 001946
- to stream Main, to step Merge: 004694
- to stream Main, to step Curation: 003F72
- to stream Main, to step Exploration: 003F72
- to stream France, to step Extraction: 000332
Links to Exploration step
ISTEX:620D762106DF55C0FF897167111CF8848335AB6ALe document en format XML
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<front><div type="abstract">The size of the (CAG)n repeat array in the 3′ end of the MJDI gene and the haplotype at a series of microsateilite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD). Our data provide five novel observations. First, MJD is associated with expansion of the array from the normal range of 14–37 repeats to 68–84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups. Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meloses, and this instability was associated with the clinical phenomenon of anticipation. Third, the size of the expanded allele is not only Inversely correlated with the age-of-onset of MJD (r=−0.738, p<0.001), but is also correlated with the frequency of other clinical features [e.g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with larger repeats (p<0.001 and p>0.05 respectively)]. Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD. Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.</div>
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<name sortKey="Yuasa, T" sort="Yuasa, T" uniqKey="Yuasa T" first="T." last="Yuasa">T. Yuasa</name>
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<country name="Canada"><region name="Ontario"><name sortKey="Kennedy, J L" sort="Kennedy, J L" uniqKey="Kennedy J" first="J. L." last="Kennedy">J. L. Kennedy</name>
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<name sortKey="Lang, A E" sort="Lang, A E" uniqKey="Lang A" first="A. E." last="Lang">A. E. Lang</name>
<name sortKey="St George Hyslop, P H" sort="St George Hyslop, P H" uniqKey="St George Hyslop P" first="P. H." last="St George-Hyslop">P. H. St George-Hyslop</name>
<name sortKey="Wherrett, J R" sort="Wherrett, J R" uniqKey="Wherrett J" first="J. R." last="Wherrett">J. R. Wherrett</name>
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<country name="France"><region name="Île-de-France"><name sortKey="Weissenbach, J" sort="Weissenbach, J" uniqKey="Weissenbach J" first="J." last="Weissenbach">J. Weissenbach</name>
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<country name="États-Unis"><region name="Connecticut"><name sortKey="Kidd, K K" sort="Kidd, K K" uniqKey="Kidd K" first="K. K." last="Kidd">K. K. Kidd</name>
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