Genetics and Genome Biology, The Hospital for Sick Children, TMDT Building 101 College Street, 15th Floor, Rm 15-312 East Tower, Toronto, ON M5G 1L7, Canada.
J Med Genet. 2011 Jul;48(7):438-43. doi: 10.1136/jmg.2010.085944. Epub 2011 May 27.
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.
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.
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.
This non-CTG configuration expands current understanding of the sequence variations that can arise at this hypermutable site.
最近，在 1 型肌强直性营养不良（DM1）基因座的（CTG）n 重复序列中报告了一些有趣的突变。例如，该重复序列曾被长期认为是一个纯重复序列，但现在在一些扩展病例中发现它通常含有中断基序。同样，也有少数新出现的体细胞 CTG 扩展是从认为遗传稳定的 5-37 个单位的非扩展 DM1 等位基因中产生的。
本研究描述了一种新的 DM1 CTG 重复突变构型，该突变在一个青少年起病的 DM1 患者中呈体细胞嵌合现象，该患者的非扩展等位基因（CTG）12 存在组织特异性扩展，范围从（CTG）1100 到 6000。
该突变构型用 43 或 60 个核苷酸的非 CTG 重复插入取代了 CTG 序列，其位置精确地位于 CTG 序列的位置，侧翼序列正确。这些插入似乎来自染色体 4q12 上的一个较长的人类序列，可能是通过 DNA 结构介导的基因间重组或复制/修复模板转换错误而产生的。在大脑皮层和骨骼肌中检测到了新的插入，但在心脏或肝脏中没有检测到。在小脑中还检测到了带有-1 或-2 CTG 单位的重复序列，这可能是由于短（CTG）12 等位基因的收缩而产生的。
这种非 CTG 结构扩展了当前对这个高突变位点可能产生的序列变异的理解。
