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Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin alpha2-chain in congenital muscular dystrophy with partial deficiency of the protein



Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin alpha2-chain in congenital muscular dystrophy with partial deficiency of the protein



American Journal of Human Genetics 58(6): 1177-1184



Congenital muscular dystrophies (CMDs) are autosomal recessive muscle disorders of early onset. Approximately half of CMD patients present laminin alpha-2-chain (merosin) deficiency in muscle biopsies, and the disease locus has been mapped to the region of the LAMA2 gene (6q22-23) in several families. Recently, two nonsense mutations in the laminin alpha-2-chain gene were identified in CMD patients exhibiting complete deficiency of the laminin alpha-2-chain in muscle biopsies. However, a subset of CMD patients with linkage to LAMA2 show only partial absence of the laminin alpha-2-chain around muscle fibers, by immunocytochemical analysis. In the present study we have identified a homozygous missense mutation in the alpha-2-chain gene of a consanguineous Turkish family with partial laminin alpha-2-chain deficiency. The T-C transition at position 303S in the cDNA sequence results in a Cys996 fwdarw Arg substitution. The mutation that affects one of the conserved cysteine-rich repeats in the short arm of the laminin alpha-2-chain should result in normal synthesis of the chain and in formation and secretion of a heterotrimeric laminin molecule. Muscular dysfunction is possibly caused either by abnormal disulfide cross-links and folding of the laminin repeat, leading to the disturbance of an as yet unknown binding function of the laminin alpha-2-chain and to shorter half-life of the muscle-specific laminin-2 and laminin-4 isoforms, or by increased proteolytic sensitivity, leading to truncation of the short arm.

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Accession: 009485143

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PMID: 8651294


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