Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype

Shelbourne, Peggy; Winqvist, Robert; Kunert, E.; Davies, June; Leisti, J; Thiele, Hannelore; Bachmann, H; Buxton, Jessica L.; Williamson, Bob; Johnson, Keith

doi:10.1093/hmg/1.7.467

Cited by 92 publications

(31 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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: 76%

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

Graaff¹,

Rouillard

Willems

et al. 1995

Human Molecular Genetics

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 76%

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

Graaff¹,

Rouillard

Willems

et al. 1995

Human Molecular Genetics

View full text Add to dashboard Cite

show abstract

“…Furthermore, a few DM1 families have been shown to preferentially pass on repeat contractions of the expanded repeat to subsequent generations (2)(3)(4)(5). It is unknown how and when these deletions arise.…”

Section: Discussionmentioning

confidence: 99%

“…Tracts that are Ն34 can be genetically unstable, and expansions can be as large as 3000 repeats. In affected families there is a common tendency for expansion of the disease allele, although there have been a few DM1 families reported that preferentially transmit repeat contractions to subsequent generations (2)(3)(4)(5). Dramatic differences in CTG length variations have been observed in several regions of the brain in DM1, HD, and DRPLA patients when compared with blood of the same patient (1).…”

mentioning

confidence: 99%

Fidelity of Primate Cell Repair of a Double-strand Break within a (CTG)·(CAG) Tract

Marcadier

Pearson

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

At least 15 human diseases are caused by the instability of gene-specific (CTG)⅐(CAG) repeats. The precise mechanism of instability remains unknown, though bacterial and yeast models have suggested a role for aberrant repair of double-strand breaks (DSBs). Using an established primate DSB repair system, we have investigated the fidelity of repair of a DSB within a (CTG)⅐(CAG) repeat tract. DSB repair substrates were generated from plasmids that are stably replicated in their circular form, permitting us to highlight the effects of DSB repair on repeat stability and minimize the contribution of replication. DSBs were introduced into repeat-containing plasmids using a unique BsmI site, such that the entire repeat tract comprised one free end of the linearized plasmid. Substrates containing 17, 47, and 79 repeats, in either their linear duplex form or containing slipped structures (out-of-register interstrand mispairings at repeat sequences), were transiently transfected into primate cells. Linearized plasmids with repeats were repaired with mildly reduced efficiency, while the presence of slipped structures considerably reduced repair efficiency. The repaired products were characterized for alterations within the repeat tract and flanking sequence. DSB repair induced predominantly repeat deletions. Notably, a polarized/ directional deletion effect was observed, in that the repetitive end of the DSB was preferentially removed. This phenomenon was dramatically enhanced when slipped structures were present within the repeat tract, providing the first evidence for error-prone processing of slipped-strand structures. These results suggest the existence of primate nuclease activities that are specific for (CTG)⅐(CAG) repeats and the structures they form.

show abstract

“…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%

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

et al. 2000

View full text Add to dashboard Cite

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.

show abstract

Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype

Cited by 92 publications

References 0 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

Fidelity of Primate Cell Repair of a Double-strand Break within a (CTG)·(CAG) Tract

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

Contact Info

Product

Resources

About