A single point mutation in the LN domain of LAMA2 causes muscular dystrophy and peripheral amyelination.

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Amino-Acid-Sequence, Animals, Basement-Membrane, Disease-Models-Animal, Laminin, Mice-Mutant-Strains, Microscopy-Electron-Transmission, Molecular-Sequence-Data, Muscle-Fibers, Muscle-Skeletal, Muscular-Dystrophy-Animal, Myelin-Sheath, Neuromuscular-Junction, Point-Mutation, Protein-Structure-Tertiary, Schwann-Cells, Spinal-Nerve-Roots

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J Cell Sci 2008 May; 121(pt 10):1593-604.


Mutations in the gene encoding the basal lamina (BL) component laminin alpha2 (LAMA2) cause merosin-deficient congenital muscular dystrophy 1A (MDC1A), a complex disorder that includes hypomyelination and myodegeneration. In dystrophia muscularis (dy) mice bearing Lama2 mutations, myofibers and Schwann cells fail to assemble stable BLs, which are thought to be crucial for myofiber survival and Schwann cell differentiation. Here, we describe defects in a new allele of Lama2 in mice, nmf417, in which a point mutation substitutes Arg for Cys79 at a universally conserved CxxC motif in the laminin N-terminal (LN) domain; this domain mediates laminin-laminin interactions. nmf417 homozygosity caused progressive myodegeneration and severe peripheral amyelination in nerve roots, similar to previous Lama2 mutations, but without the pervasive BL thinning previously associated with the disorder. In direct contrast to the previously characterized dy and dy2J alleles, nmf417 homozygous myofibers frequently had thickened BLs. Severe amyelination in nmf417-mutant nerve roots suggested complete laminin 2 inactivation for Schwann cells, although myelinated fibers had normal BLs. The results reveal crucial roles for the LN domain CxxC motif in both nerve and muscle, but challenge expected relationships between LN-domain function, Ln2 activity and BL stability. The nmf417 mutation provides a defined animal model in which to investigate mechanisms and treatments for moderate forms of MDC1A.