Reduction in Size of the Myotonic Dystrophy Trinucleotide Repeat Mutation During Transmission

O'Hoy, K; Tsilfidis, Catherine; Mahadevan, Mani S.; Neville, Catherine; Barceló, Juana; Hunter, Alasdair G. W.; Korneluk, Robert G.

doi:10.1126/science.8094260

Cited by 99 publications

(44 citation statements)

References 18 publications

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“…Decrease from a full mutation to a premutation has been reported only once (15), whereas the reverse mutation, from full mutation to a normal allele has not yet been described. This is in contrast to the CTG repeat in myotonic dystrophy, in which a number of independent reverse mutations have already been described (19)(20)(21).…”

Section: Introductionmentioning

confidence: 79%

Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients

Graaff¹,

Rouillard

Willems

et al. 1995

Human Molecular Genetics

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The fragile X syndrome is the most frequent cause of inherited mental retardation. The molecular mechanism of the disorder is based on the expansion of a CGG repeat in the 5' UTR of the FMR1 gene in the majority of fragile X patients. The instability of this CGG repeat containing region is not restricted to the CGG repeat itself but expands to the flanking region as well. We describe four unrelated fragile X patients that are mosaic for both a full mutation and a small deletion in the CGG repeat containing region. Sequence analysis of the regions surrounding the deletions showed that both the (CGG)n repeat and some flanking sequences were missing in all four patients. The 5' breakpoints of the deletions were found to be located between 75-53 bp proximal to the CGG repeat. This suggests the presence of a hot spot region for deletions in the CGG repeat region of the FMR1 gene and emphasizes the instability of this region in the presence of an expanded CGG repeat.

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Section: Introductionmentioning

confidence: 79%

Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients

Graaff¹,

Rouillard

Willems

et al. 1995

Human Molecular Genetics

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“…26 Recently, gene conversion was proposed as the mechanism involved in the origin of a rare intermediate allele of MJD, as it had a flanking SNP-based haplotype (A -C -A) commonly observed in large alleles and, simultaneously, a tract variant at the sixth repeat (CAA instead of CAG), only observed in smaller alleles that were significantly associated with a different SNP-based haplotype (G -G -C). 27 As for other CTG Á CAG tracts, gene conversion was reported in a few clinical cases of myotonic dystrophy (MD) 28,29 and Huntington disease, 30 whereas other alternative models for the evolution of wild-type alleles have been hypothesized. In Friedreich ataxia, two duplication events were suggested to explain the distribution of GAA repeat sizes observed in normal chromosomes.…”

Section: Discussionmentioning

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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“…All samples showed twotailed distributions with a lower tail extending back down into the normal size range, consistent with a germline specific mutational pathway that generates a low but detectable fraction of reversions, in good agreement with the rate of reversions observed in DM1 pedigrees. [21][22][23] In addition, the threshold for gross instability appears to be much lower in the male germline than in the soma. These data confirm that the male germline mutational pathway is very different from that observed in somatic tissues where such revertant alleles are observed only very rarely.…”

Section: Discussionmentioning

confidence: 99%

“…Although meiosis is an obvious candidate, there is little direct evidence to confirm this other than the correlation of one of the observed reversions with a complex gene conversion event. 22 Nonetheless, given the high levels of somatic instability observed for large expansions, it seems likely that any meiotic effect would be superimposed upon a premeiotic effect. One factor The progenitor allele length, and hence the average length change per sperm and contraction frequencies, were estimated from the lower boundary of the distribution observed in the somatic DNA (see text for details).…”

Section: Discussionmentioning

confidence: 99%

Complex patterns of male germline instability and somatic mosaicism in myotonic dystrophy type 1

et al. 2000

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The genetic basis of myotonic dystrophy type 1 (DM1) is the expansion of a CTG repeat in the 3' untranslated region of DM1PK. Once into the disease range, the repeat becomes highly unstable and is biased toward expansion in both somatic and germline tissues. Intergenerational differences usually reveal an increase in allele length, concordant with the clinical anticipation characteristic of DM1, but there have also been cases with intergenerational contractions of the repeat length, accompanied by apparent anticipation. In order to gain a better understanding of this intergenerational behaviour, we have obtained semen samples from six DM males and used single molecule analyses to compare the allele distributions present in their sperm and blood with those of their offspring. We have confirmed that the male germline mutational pathway is distinct from that of the soma, but the extent of variation is highly variable from one individual to another and not obviously correlated with progenitor allele length. Nonetheless, in all cases the alleles present in the father's sperm overlap with those observed in their offspring. These data also provide further indications that the interpretation of intergenerational transmissions by standard analyses is frequently compromised by the masking of germline differences by age-dependent somatic expansion in the parent.

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Reduction in Size of the Myotonic Dystrophy Trinucleotide Repeat Mutation During Transmission

Cited by 99 publications

References 18 publications

Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients

Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients

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

Complex patterns of male germline instability and somatic mosaicism in myotonic dystrophy type 1

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