Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures

Abstract

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.

Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC International Workshop, 23–24 November 2001, Naarden, The Netherlands

“…It is caused by dominant mutations in COL6A1 (OMIM # 120220), COL6A2 (OMIM # 120240) [4], and COL6A3 (OMIM # 120250) [5] genes.…”

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…lampe and Bushby 69 summarized the most frequent pathogenic mechanisms in Bethlem myopathy: single amino acid substitutions disrupting the Gly-Xaa-yaa motif of the triple helical domain in Col6A1, Col6A2, or Col6A3 77,121,127,130 ,and splice site mutations 75,121,125,128 which cause skipping of Col6A1 exon 14 during pre-mrNA splicing and consequently in-frame deletion of 18 amino acids from the triple helical domain of the a1 chain. In the first case, mutations towards the N terminal region of the triple helix may cause kinking of the tetramers in the normally straight supercoiled triple helical region, thus reducing their ability to form microfibrils 127 and exerting a dominant negative effect.…”

“…3), and Col6A3 (2 q37) that encode respectively the alpha-1, alpha-2 and alpha-3 chains of collagen VI, cause two types of muscle disorders: Bethlem myopathy, with mild or moderate phenotype, and Ullrich CMD, with severe phenotype [1][2][3][4]6,7,69,117 . Bethlem myopathy is a slowly progressive disorder with variable age of onset, congenital or within the first or second decade of life, and marked flexion contractures of several joints 7,69,76,77,[117][118][119] . Ullrich CMD is an early onset condition with severe weakness and progressive course that manifests proximal joint contractures and marked distal hyperlaxity.…”

“…Mutations in the genes that codify the three collagen VI subunits lead to the second most common form of CMD, Ullrich atonic-sclerotic CMD [72][73][74][75] and to Bethlem myopathy 76,77 that now is included into CMD classification 8 .…”

Type VI Collagen Anchors Endothelial Basement Membranes by Interacting with Type IV Collagen

“…Mutations in type VI collagen give rise to Bethlem myopathy, whose major clinical feature is weakening of the muscles (29,30). Fig.…”