Molecular pathogenesis of peripheral dysmyelination common to laminin-2 deficient muscular dystrophy and leprosy

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Dysfunction of the dystroglycan (DG) complex is presumed to play a role in peripheral dysmyelination which is characteristically observed in both laminin-2 deficient congenital muscular dsytrophy and leprosy. In this study, we attempted to clarify its molecular pathogenesis and obtained the following results. (1) DG expression increased concomittant with the initiation of Schwann cell myelination in peripheral nerve. (2) DG expression decreased with degeneration and increased with regeneration of peripheral nerve. (3) A matrix metalloproteinase activity was identified that disrupts the link between the basal lamina and cell membrane via the DG complex by cleaving the extracellular domain of βDG. (4) A novel laminin-binding protein homologus to mammalian 30 kDa laminin-binding protein LBP30 was identified in the cell wall of Mycobacterium leprae and suspected to mediate host cell infection by the bacteria. (5) A transgenic mice with defects in the gene of caveolin-3 that functionally interacts with the DG complex was generated. The animals displayed a phenotype of severe muscular dsytrophy together with abnormal nNOS activity in muscle. (6) A 180 kDa extracellular matrix protein p180 was deficient in the muscle of Fukuyama type congential muscular dystrophy patients. In the nervous system, p180 was co-localized with the DG complex in the glia limitans basal lamina complex in brain and surrounding Schwall cell outer membrane in peripheral nerve. All together, these results indicate that dysfunction of the DG complex is involved in the molecular pathogenesis of nervous system defects such as peripheral dysmyelination and its modification may be effective as a therapy to correct these abnormalities.