Journal
JOURNAL OF MEDICAL GENETICS
Volume 48, Issue 7, Pages 438-443Publisher
B M J PUBLISHING GROUP
DOI: 10.1136/jmg.2010.085944
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Funding
- Canadian Institutes of Health Research (CIHR)
- Muscular Dystrophy Canada
- University of Rochester Paul Wellstone Muscular Dystrophy Cooperative Research Center
- NIH [U54NS48843]
- Muscular Dystrophy Association USA (MDAUSA)
- Ontario Graduate Scholarship
- Hospital for Sick Children Research Training Centre
- Cell Science Research Foundation
- Uehara Memorial Foundation
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Background Recently, curious mutations have been reported to occur within the (CTG)n repeat tract of the myotonic dystrophy type 1 (DM1) locus. For example, the repeat, long presumed to be a pure repeat sequence, has now been revealed to often contain interruption motifs in a proportion of cases with expansions. Similarly, a few de novo somatic CTG expansions have been reported to arise from non-expanded DM1 alleles with 5-37 units, thought to be genetically stable. Aims and methods This study has characterised a novel mutation configuration at the DM1 CTG repeat that arose as somatic mosaicism in a juvenile onset DM1 patient with a non-expanded allele of (CTG) 12 and tissue specific expansions ranging from (CTG) 1100 to 6000. Results The mutation configuration replaced the CTG tract with a non-CTG repeat insertion of 43 or 60 nucleotides, precisely placed in the position of the CTG tract with proper flanking sequences. The inserts appeared to arise from a longer human sequence on chromosome 4q12, and may have arisen through DNA structure mediated somatic inter-gene recombination or replication/repair template switching errors. De novo insertions were detected in cerebral cortex and skeletal muscle, but not in heart or liver. Repeat tracts with -1 or -2 CTG units were also detected in cerebellum, which may have arisen by contractions of the short (CTG) 12 allele. Conclusion This non-CTG configuration expands current understanding of the sequence variations that can arise at this hypermutable site.
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