Jöbsis G J, Keizers H, Vreijling J P, de Visser M, Speer M C, Wolterman R A, Baas F, Bolhuis P A
Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands.
Nat Genet. 1996 Sep;14(1):113-5. doi: 10.1038/ng0996-113.
Among the diverse family of collagens, the widely expressed microfibrillar type VI collagen is believed to play a role in bridging cells with the extracellular matrix. Several observations imply substrate properties for cell attachment as well as association with major collagen fibers. Previously, we have established genetic linkage between the genes encoding the three constituent alpha-chains of type VI collagen and Bethlem myopathy. A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints in addition to generalized muscular weakness and wasting. Nine kindreds show genetic linkage to the COL6A1-COL6A2 cluster on chromosome 21q22.3 (refs 3,4; manuscript submitted) whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3 (ref. 5). Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other kindreds. Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser. Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the alpha 2-subunit of laminin, our observations suggest a similar mechanism in Bethlem myopathy.
在多样的胶原蛋白家族中，广泛表达的微原纤维VI型胶原蛋白被认为在细胞与细胞外基质的连接中发挥作用。一些观察结果表明其具有细胞附着的底物特性以及与主要胶原纤维的关联。此前，我们已确定编码VI型胶原蛋白三条组成α链的基因与贝斯勒姆肌病之间存在遗传连锁关系。这种常染色体显性疾病的一个显著特征除了全身性肌肉无力和萎缩外，还包括多个关节的挛缩。九个家系显示与21号染色体21q22.3上的COL6A1 - COL6A2基因簇存在遗传连锁关系（参考文献3、4；手稿已提交），而一个家族显示与2号染色体2q37上靠近COL6A3的标记存在连锁关系（参考文献5）。对四个家系的序列分析显示，一个家系的COL6A1存在突变，另外两个家系的COL6A2存在突变。这两种突变均通过将甘氨酸替换为缬氨酸或丝氨酸破坏了三螺旋结构域的甘氨酸 - X - 酪氨酸基序。类似于先天性肌营养不良中由于层粘连蛋白α2亚基突变导致的肌营养不良蛋白相关复合物锚定功能的假定扰动，我们的观察结果表明贝斯勒姆肌病存在类似机制。
