Faculty of Biology, Center for Human Molecular Genetics, University of Belgrade, Studentski trg 16, PO Box 43, Belgrade, 11000, Serbia.
Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotica 6-8, Belgrade, 11000, Serbia.
Neurogenetics. 2017 Dec;18(4):207-218. doi: 10.1007/s10048-017-0523-7. Epub 2017 Sep 23.
Myotonic dystrophy type 1 (DM1) is caused by a highly unstable expansion of CTG repeats in the DMPK gene. Its huge phenotypic variability cannot be explained solely by the repeat number. Recently, variant repeats within the DMPK expansions have emerged as potential disease modifiers. The frequency of variant expanded alleles was estimated in 242 DM1 patients from 174 Serbian families using repeat-primed PCR (RP-PCR). The patterns of variant repeats were determined by direct sequencing of RP-PCR or PCR products. PCR-based southern blot was performed to get insight into the intergenerational mutational dynamics of variant expanded alleles. All patients carrying variant repeats were clinically re-examined. Variant repeats were observed in eight patients from five families (2.9%). They were detected only at the 3' end of DMPK expansions. CCG variant repeats were present in seven patients, either as a part of regular runs of CCGCTG hexamer, individual repeats, or CCG blocks. Analyses of three intergenerational transmissions revealed a considerable stability or likely a contraction of variant expanded alleles. Intriguingly, a decrease in age at onset accompanied these transmissions. Overall, patients were characterized by a milder phenotype and/or some atypical symptoms that could be rather clinically suggestive of myotonic dystrophy type 2. In addition, the first case of de novo CTC variant repeat was observed. Variant repeats might explain a part of the phenotypic variability in a small percent of DM1 patients and likely display a stabilizing effect on the meiotic instability of DMPK expanded alleles.
肌强直性营养不良 1 型（DM1）是由 DMPK 基因中的 CTG 重复序列高度不稳定扩增引起的。其巨大的表型变异性不能仅用重复数来解释。最近，DMPK 扩增内的变体重复序列已成为潜在的疾病修饰因子。使用重复引物 PCR（RP-PCR），在来自 174 个塞尔维亚家族的 242 名 DM1 患者中估计了变体扩增等位基因的频率。通过直接测序 RP-PCR 或 PCR 产物确定了变体重复的模式。进行基于 PCR 的 Southern blot 以深入了解变体扩增等位基因的代际突变动态。对携带变体重复的所有患者进行了临床复查。在五个家族的八名患者（2.9%）中观察到变体重复。它们仅在 DMPK 扩增的 3' 端检测到。七个患者存在 CCG 变体重复，要么作为 CCGCTG 六聚体的规则重复、单个重复或 CCG 块的一部分。对三个代际传递的分析显示，变体扩增等位基因具有相当的稳定性或可能收缩。有趣的是，这些传递伴随着发病年龄的降低。总体而言，患者的表型较轻，/或存在一些非典型症状，这可能提示为肌强直性营养不良 2 型。此外，还观察到了首例 CTC 变体重复的从头发生。变体重复可能解释了一小部分 DM1 患者表型变异性的一部分，并可能对 DMPK 扩增等位基因的减数分裂不稳定性表现出稳定作用。
