Skeletal muscle laminin and MDC1A: pathogenesis and treatment strategies

The basement membrane is a thin scaffold of specific extracellular protein networks associated with various cell types, including muscle fibers. This specialized framework of extracellular matrix (ECM) provides important functional cues to cells. Laminins comprise a family of glycoproteins that are major components of all basement membranes [1]. Occurrence of a laminin molecule in hydra, one of the oldest multicellular organisms, indicates that laminins existed already 600 million years ago [2]. Laminins are large (400-900 kDa) heterotrimeric molecules composed of one α, one β and one γ subunit in a cruciform or T-shaped appearance. To date, five α, three β and three γ chains have been characterized. They represent the products of distinct genes that evolved by duplication and recombination of ancestral α, β and γ genes, hence they share sequence similarity. Currently, the trimers are named according to the composition of the α, β and γ chains and more than 15 different laminin isoforms, with various arrangements of laminin subunits, have been identified [3-5]. The first laminin isoform, laminin-111, was discovered more than 30 years ago in the Engelbreth-Holm-Swarm tumor [6]. Subsequently, laminin-211 (composed of α2, β1 and γ1 chains) (Figure 1) was isolated from placenta and was originally called merosin [7]. It is now well established that laminin-211 is the main laminin isoform in skeletal muscle [8,9], and identification of laminin α2 chain mutations in a severe form of congenital muscular dystrophy (merosin-deficient congenital muscular dystrophy; MDC1A) showed the importance of laminin-211 for normal muscle function [10].The LAMA2 gene is located on chromosome 6q22-23 in humans and on chromosome 10 in mice [10-12]. The gene is composed of 65 exons that encode a protein with a predicted molecular mass of 390 kDa. However, it is cleaved by a furin-like convertase into a 300 kDa N-terminal segment and a 80 kDa C-terminal segment, which remain non-covalently ass