Deficiency of
laminin alpha2 is the cause of one of the most severe
muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the
laminin alpha2 chain gene affect
protein expression, and how abnormal levels or structure of the
protein affect disease. Animal models may be valuable for such genotype-phenotype analysis and for determining mechanism of disease as well as function of
laminin. Here, we have analyzed
protein expression in three lines of mice with mutations in the
laminin alpha2 chain gene and in two lines of transgenic mice overexpressing the human
laminin alpha2 chain gene in skeletal muscle. The dy(3K)/dy(3K) experimental mutant mice are completely deficient in
laminin alpha2; the dy/dy spontaneous mutant mice have small amounts of apparently normal
laminin; and the dy(W)/dy(W) mice express even smaller amounts of a truncated
laminin alpha2, lacking domain VI. Interestingly, all mutants lack
laminin alpha2 in peripheral nerve. We have demonstrated previously, that overexpression of the human
laminin alpha2 in skeletal muscle in dy(2J)/dy(2J) and dy(W)/dy(W) mice under the control of a striated muscle-specific
creatine kinase promoter substantially prevented the
muscular dystrophy in these mice. However, dy(W)/dy(W) mice, expressing the human
laminin alpha2 under the control of the striated muscle-specific portion of the
desmin promoter, still developed
muscular dystrophy. This failure to rescue is apparently because of insufficient production of
laminin alpha2. This study provides additional evidence that the amount of
laminin alpha2 is most critical for the prevention of
muscular dystrophy. These data may thus be of significance for attempts to treat congenital
muscular dystrophy in human patients.