University of Utah, Departments of Pediatrics and Neurology, Salt Lake City, Utah.
Hum Mutat. 2013 Nov;34(11):1558-67. doi: 10.1002/humu.22429.
Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix.
甘氨酸取代胶原六聚体三螺旋（TH）结构域中的保守 Gly-X-Y 基序是胶原六聚体肌病（包括 Ullrich 先天性肌营养不良症、Bethlem 肌病和中间（INT）表型）中最常见的突变。我们描述了 97 名 COL6A1、COL6A2 或 COL6A3 的 TH 结构域中存在甘氨酸取代的个体的临床和遗传特征，并对 97 例已发表病例进行了综述，总计 194 例病例。临床发现包括严重、INT 和轻度表型，即使是具有相同突变的患者也是如此。INT 表型最为常见，占近一半的患者，这强调了 INT 表型对整体表型谱的重要性。TH 结构域中的甘氨酸取代严重聚集在第 17 个 Gly-X-Y 三肽的 N 端短片段中，这些取代作为显性突变。最严重的病例聚集在一个更小的区域，包括 Gly-X-Y 三肽 10-15，仅占 TH 结构域的 5%。我们的研究结果表明，胶原六聚体 N 端区域甘氨酸取代的聚集不是基于一级序列的特征。我们假设该区域可能代表三螺旋内的一个功能域。
