Pan T C, Zhang R Z, Pericak-Vance M A, Tandan R, Fries T, Stajich J M, Viles K, Vance J M, Chu M L, Speer M C
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Hum Mol Genet. 1998 May;7(5):807-12. doi: 10.1093/hmg/7.5.807.
The Bethlem myopathy is a rare autosomal dominant proximal myopathy characterized by early childhood onset and joint contractures. Evidence for linkage and genetic heterogeneity has been established, with the majority of families linked to 21q22.3 and one large family linked to 2q37, implicating the three type VI collagen subunit genes, COL6A1 (chromosome 21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes. Mutations of the invariant glycine residues in the triple-helical domain-coding region of COL6A1 and COL6A2 have been reported previously in the chromosome 21-linked families. We report here the identification of a G-->A mutation in the N-terminal globular domain-coding region of COL6A3 in a large American pedigree (19 affected, 12 unaffected), leading to the substitution of glycine by glutamic acid in the N2 motif, which is homologous to the type A domains of the von Willebrand factor. This mutation segregated to all affected family members, to no unaffected family members, and was not identified in 338 unrelated Caucasian control chromosomes. Thus mutations in either the triple-helical domain or the globular domain of type VI collagen appear to cause Bethlem myopathy.
贝斯勒姆肌病是一种罕见的常染色体显性遗传性近端肌病，其特征为发病于儿童早期并伴有关节挛缩。连锁分析和遗传异质性的证据已经确立，大多数家系与21q22.3连锁，一个大家系与2q37连锁，这表明VI型胶原的三个亚基基因，即COL6A1（21号染色体）、COL6A2（21号染色体）和COL6A3（2号染色体）是候选基因。先前在与21号染色体连锁的家系中已报道了COL6A1和COL6A2三螺旋结构域编码区中不变甘氨酸残基的突变。我们在此报告在一个美国家系（19名患者，12名未患病者）中COL6A3的N端球状结构域编码区鉴定出一个G→A突变，导致N2基序中的甘氨酸被谷氨酸取代，该基序与血管性血友病因子的A型结构域同源。此突变在所有患病家族成员中分离，未患病家族成员中无此突变，且在338条无关的白种人对照染色体中未发现。因此，VI型胶原三螺旋结构域或球状结构域中的突变似乎都会导致贝斯勒姆肌病。
