Linkage Disequilibrium between the Spinocerebellar Ataxia 3/Machado‐Joseph Disease Mutation and Two Intragenic Polymorphisms, One of Which, X359Y, Affects the Stop Codon

Stevanin, Giovanni; Lebre, Anne‐Sophie; Mathieux, Cecile; Cancel, Géraldine; Abbas, Nacer; Didierjean, Olivier; Dürr, Alexandra; Trottier, Yvon; Agid, Yves; Brice, Alexis

doi:10.1086/523993

Cited by 8 publications

(27 citation statements)

References 14 publications

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“…When the association between (CAG) n length and the C 987 GG/G 987 GG polymorphism polymorphism were detected among longer repeats. It is interesting, however, that in our study as well as the two previous studies 17,32 there was no exclusive association of the larger alleles with any allele of the polymorphisms in the population of Portuguese origin, in contrast with the observations in populations of other ethnic origins (French and Japanese, but not North African). In terms of the intragenic haplotypes defined by these polymorphisms, four different haplotypes were found among the group of larger normal alleles in our population.…”

Section: Discussioncontrasting

confidence: 80%

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract

et al. 1999

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Intergenerational instability is one of the most important features of the disease-associated trinucleotide expansions, leading to variation in size of the repeat among and within families, which manifests as variable age at onset and severity, and is probably the basis for the occurrence of anticipation. Several factors are known to affect the degree of instability, namely the type of repeated sequence, its initial size, the presence or absence of interruptions in the repetitive tract and the gender of the transmitting parent. A recent study demonstrated the effect of an intragenic polymorphism (C 987 GG/G 987 GG) in the Machado-Joseph disease causative gene, immediately downstream of the CAG repeat, on the intergenerational instability of the expanded repeat. Surprisingly, there was an effect not only of the specific allele in cis to the disease chromosome, but also of the allele on the normal chromosome, suggesting the existence of an interaction between the normal and expanded alleles that affects the fidelity of replication of the (CAG) n tract. This effect could be a direct effect of the polymorphism studied or, alternatively, this polymorphism could be in disequilibrium with some other flanking sequence which affects the instability of the repetitive (CAG) n tract. In order to confirm the previous results in a different population and to distinguish between a direct and indirect effect of the CGG/GGG polymorphism, we typed 70 parent-progeny pairs for which the variation in the (CAG) n length in the MJD1 gene was known, for three intragenic polymorphisms: C European Journal of Human Genetics (1999) 7, 147-156 © 1999 Stockton Press All rights reserved 1018-4813/99 $12.00 t http://www.stockton-press.co.uk/ejhg suggestive of an instability-predisposing effect of the repeat-flanking sequences, which could have led to the origin of the MJD mutation in the human population. We confirmed the effect of the C 987 GG/G 987 GG polymorphism on intergenerational instability when present in trans. Our results suggest that this effect is restricted to a small region of the gene, immediately downstream of the CAG repeat, which includes this particular nucleotide substitution and the stop codon of the MJD1 cDNA, and is not a more widespread chromosomal effect. The lack of a significant association of any specific intragenic haplotype with larger CAG repeats in normal chromosomes, together with the absence of an effect of the intragenic haplotype in cis on the intergenerational instability of the expanded (CAG) n in MJD families does not indicate the existence of an instability-predisposing haplotype.

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Section: Discussioncontrasting

confidence: 80%

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract

et al. 1999

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“…20 Results from sequencing have shown three pure and one complex interrupted polymorphic marker (allelic frequencies for each population are reported in Supplementary material -S2). The complex (GT) n repeat presented perfect (GT) 14 , (GT) 15 , (GT) 17 and (GT) 18 alleles, whereas Multistep mutation mechanism at MJD/SCA3 locus S Martins et al interrupted alleles 13, 19 and 16 had the motifs (GT) 4;10 AT (GT) 5 GG (GT) 2 and (GT) 13 GG (GT) 2 , respectively.…”

Section: Molecular Distances Among Cag Allelesmentioning

confidence: 99%

A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus

et al. 2006

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Despite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range that, ultimately, expand to pathological size. In this study, we assessed the mutation mechanisms by which wild-type Machado -Joseph disease (MJD) alleles have been generated throughout human evolution. Haplotypes including the CAG repeat, six intragenic SNPs and four flanking microsatellites were analysed in 431 normal chromosomes of European, Asian and African origin. A bimodal CAG repeat length frequency distribution was found in the four most frequent wild-type lineages (H1-GCGGCA; H2-GTGGCA; H3-TTAGAC and H4-TTACAC). Based on flanking microsatellite haplotypes, the variance calculated by analysis of molecular variance between modal (CAG) n alleles was little or null in lineages H1, H2 and H4, as were the pairwise differences. Moreover, genetic distances among all the alleles from each lineage did not reflect the allele sizes differences, as expected if a stepwise mutation model was the main process of evolution. On the contrary, when exposed in maximum parsimonious phylogenetic trees, a large number of mutation steps separated same-size alleles, whereas several microsatellite haplotypes were shared by modal CAGs. In conclusion, our results suggest that the main mutation mechanism occurring in the evolution of the polymorphic CAG region at MJD/SCA3 locus is a multistep one, either by gene conversion or DNA slippage; repeats with 14, 21, 23 and 27 CAGs are the main alleles involved in this process.

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“…36 Furthermore, large normal alleles and disease-linked chromosomes in SCA3 and DRPLA share similar haplotypes. 31,37 Do IAs share haplotypes with the SCA7 mutations?…”

Section: Relation Between Ia and Sca7-linked Haplotypesmentioning

confidence: 99%

Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by linkage disequilibrium studies with closely flanking markers, including an intragenic polymorphism (G3145TG/A3145TG)

et al. 1999

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Linkage Disequilibrium between the Spinocerebellar Ataxia 3/Machado‐Joseph Disease Mutation and Two Intragenic Polymorphisms, One of Which, X359Y, Affects the Stop Codon

Cited by 8 publications

References 14 publications

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract

A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus

Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by linkage disequilibrium studies with closely flanking markers, including an intragenic polymorphism (G3145TG/A3145TG)

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