Research Centre for Medical Genetics, Moscow 115478, Russia; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia.
Research Centre for Medical Genetics, Moscow 115478, Russia.
Gene. 2018 Sep 25;672:165-171. doi: 10.1016/j.gene.2018.06.026. Epub 2018 Jun 9.
Here we present a case report of collagen VI related myopathy in a patient, 8 y.o. boy, with intermediate phenotype between severe Ullrich congenital muscular dystrophy and milder Bethlem myopathy. Whole exome sequencing revealed two novel single nucleotide variants in COL6A3 gene: paternal p.Glu2402Ter, resulting in premature translation termination codon and degradation of mRNA from this allele probably due to nonsense-mediated decay, and maternal p.Arg1660Cys leading to amino-acid substitution in N2-terminal domain. COL6A3 expression analysis of proband's fibroblasts reveals functional homozygosity of the latter variant. Paternal fibroblasts showed only WT allele expression, which could lead to a reduction in mature transcript level, while maternal fibroblasts expressed both alleles. Functional assay of immunofluorescent staining of COL6A3 protein in fibroblasts culture reveals profound changes in COL6A3 localization and reduction of protein level in studied cultures when comparing with the controls. This study not only broadens the allelic spectrum of pathogenic COL6A3 variants in myopathy but also gives an additional support to Ullrich congenital muscular dystrophy and Bethlem myopathy clinical continuum.
在这里，我们报告了一例胶原 VI 相关肌病患者，为 8 岁男孩，具有严重的 Ullrich 先天性肌营养不良症和较轻的 Bethlem 肌病之间的中间表型。全外显子组测序显示 COL6A3 基因中有两个新的单核苷酸变异：来自父亲的 p.Glu2402Ter，导致提前出现翻译终止密码子，并且该等位基因的 mRNA 降解可能是由于无义介导的衰变引起的；来自母亲的 p.Arg1660Cys 导致 N 端结构域中的氨基酸取代。对先证者成纤维细胞的 COL6A3 表达分析显示，后者变异为功能纯合子。父亲的成纤维细胞仅表达 WT 等位基因，这可能导致成熟转录本水平降低，而母亲的成纤维细胞则表达两个等位基因。对成纤维细胞培养物中 COL6A3 蛋白的免疫荧光染色的功能测定显示，与对照组相比，COL6A3 定位发生了深刻变化，并且研究培养物中的蛋白水平降低。这项研究不仅拓宽了肌病中致病性 COL6A3 变异的等位基因谱，而且为 Ullrich 先天性肌营养不良症和 Bethlem 肌病的临床连续性提供了额外的支持。
