IDENTIFICATION OF A NOVEL MUTANT TRANSCRIPT OF LAMININ ALPHA-2 CHAIN GENE RESPONSIBLE FOR MUSCULAR-DYSTROPHY AND DYSMYELINATION IN DY(2J) MICE

Murine dystrophia muscularis-2J (dy(2J)) is an autosomal recessive disorder characterized by muscular dystrophy and dysmyelination of peripheral nerve, Biochemical characterization of dy(2J) mice revealed the expression of a mutant laminin alpha 2 chain with a smaller molecular weight in the basal lamina of striated muscle and peripheral nerve, DNA sequencing of the alpha 2 chain cDNA amplified by RT-PCR from dy(2J) mice identified a novel and predominant transcript with a 171 base in-frame deletion. We also confirmed an underlying splice donor site mutation in the alpha 2 chain gene of the dy(2J) mouse, Translation of this variant transcript would result in the expression of a truncated alpha 2 chain having a 57 amino acid deletion (residues 34-90) and a substitution of Gln91Glu in the N-terminal domain VI, which is presumed to be involved in self-aggregation of laminin heterotrimers. Thus, the mutant alpha 2 chain could disrupt the formation of the laminin network and lead to muscle cell degeneration. Our results provide a molecular basis of muscular dystrophy and dysmyelination of peripheral nerve.