title: 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.
abstract: Congenital muscular dystrophies (CMDs) are autosomal recessive muscle disorders of early onset. Approximately half of CMD patients present laminin alpha2-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 alpha2-chain gene were identified in CMD patients exhibiting complete deficiency of the laminin alpha2-chain in muscle biopsies. However, a subset of CMD patients with linkage to LAMA2 show only partial absence of the laminin alpha2-chain around muscle fibers, by immunocytochemical analysis. In the present study we have identified a homozygous missense mutation in the alpha2-chain gene of a consanguineous Turkish family with partial laminin alpha2-chain deficiency. The T-->C transition at position 3035 in the cDNA sequence results in a Cys996-->Arg substitution. The mutation that affects one of the conserved cysteine-rich repeats in the short arm of the laminin alpha2-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 alpha2-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.
authors.affiliation: Biocenter Oulu, University of Oulu, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Nissinen
authors.forename: A
authors.initials: A
authors.lastname: Helbling-Leclerc
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Evangelista
authors.forename: H
authors.initials: H
authors.lastname: Topaloglu
authors.forename: C
authors.initials: C
authors.lastname: Cruaud
authors.forename: J
authors.initials: J
authors.lastname: Weissenbach
authors.forename: M
authors.initials: M
authors.lastname: Fardeau
authors.forename: F M
authors.initials: FM
authors.lastname: Tomé
authors.forename: K
authors.initials: K
authors.lastname: Schwartz
authors.forename: K
authors.initials: K
authors.lastname: Tryggvason
authors.forename: P
authors.initials: P
authors.lastname: Guicheney
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D002675:Child, Preschool; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D003241:Consanguinity; D016384:Consensus Sequence; D017124:Conserved Sequence; D003545:Cysteine; D004247:DNA / Q000737:chemistry; D017931:DNA Primers; D004330:Drosophila; D005260:Female; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D007797:Laminin / Q000172:deficiency* / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D007797:Laminin; D004247:DNA; D003545:Cysteine