Mild muscular dystrophy due to a nonsense mutation in the LAMA2 gene resulting in exon skipping

Nonsense mutations outside the splicing consensus sequence have been report ed to cause skipping of the nonsense-containing exon in several human disea ses, We describe, for the first time, nonsense-mediated exon skipping in th e laminin alpha2 (LAMA2) gene, Two siblings from a consanguineous family ha d altered expression of the laminin alpha2 chain and moderate clinical mani festations, In both we identified the new nonsense mutation Arg744Stop, whi ch we expected to result in a totally non-functional polypeptide, However, analysis of the transcript revealed skipping of exon 15, containing the mut ation, even though the consensus sequences for splicing at both ends of the exon and the beginning of intron 15 were unaltered. Exon skipping restored the open reading frame of the mutant transcript and resulted in a truncate d protein, In cases where the genetic findings do not elucidate the phenoty pe, mRNA analysis is necessary to clarify the primary effect of mutations, Our findings also point to the necessity of immunochemical screening for ex pression of laminin alpha2 chain in atypical dystrophic adults as well as c hildren.