Abstract
Merosin deficient Congenital Muscular Dystrophy (MDC1A), or LAMA2-related muscular dystrophy (LAMA2-RD), is a recessive disorder resulting from mutations in the LAMA2 gene, encoding for the alpha-2 chain of laminin-211. The disease is predominantly characterized by progressive muscular dystrophy affecting patient motor function and reducing life expectancy. However, LAMA2-RD also comprises a developmentally-associated dysmyelinating neuropathy that contributes to the disease progression, in addition to brain abnormalities; the latter often underappreciated. In this brief review, we present data supporting the impact of peripheral neuropathy in the LAMA2-RD phenotype, including both mouse models and human studies. We discuss the molecular mechanisms underlying nerve abnormalities and involved in the laminin-211 pathway, which affects axon sorting, ensheathing and myelination. We conclude with some final considerations of consequences on nerve regeneration and potential therapeutic strategies.
Highlights
LAMA2 encodes the α2 chains of the laminin-211, a major component of the basal lamina of Schwann cells and skeletal muscles (Ehrig et al, 1990)
Loss of function mutations of the LAMA2 gene in humans, and the Laminin chain α2 gene (Lama2) gene in rodents, results in muscular dystrophy, dysmyelinating neuropathy, and brain abnormalities. This results in Merosindeficient Congenital Muscular Dystrophy (MDC1A, OMIM #607855) known as LAMA2related muscular dystrophy (LAMA2-RD)
With regards to other laminin isoforms described in peripheral nerves of Lama2 mice, the α1 chain is not expressed in wild type nerves, whereas it is reported to be upregulated in sciatic nerves of Lama2dy2J/dy2J mice (Previtali et al, 2003b), but absent in Lama2dy3K/dy3K (Gawlik et al, 2006)
Summary
LAMA2 encodes the α2 chains of the laminin-211 ( known as merosin), a major component of the basal lamina of Schwann cells and skeletal muscles (Ehrig et al, 1990). This mouse mutant shows typical Lama2 muscle and nerve pathology in the presence of normal expression (but not function) of laminin211.
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