AUTOSOMAL RECESSIVE NEUROMUSCULAR DISORDER IN A TRANSGENIC LINE OF MICE

We have generated a line of transgenic mice that when homozygous for t he transgene develop a severe, adult-onset neuromuscular disorder. Thi s mutation is likely the result of the insertional inactivation of an endogenous gene by the transgene integration. The mutant mice have a g ait abnormality with stiffened and/or splayed hind legs, and adopt a h unched posture with some exhibiting kyphosis of the thoracic spine. Th ese symptoms progress gradually to severe motor dysfunction. Pathologi c changes were found in skeletal muscle and peripheral nerve of the mu tant animals. In young mice the muscles from both upper and lower extr emities show necrosis and phagocytosis. In older mice, regeneration wi th muscle fiber splitting, internally located nuclei, and variable fib er size are conspicuous features. Interactions between Schwann cells a nd axons also appear disrupted in these animals. Although many periphe ral axons are well myelinated, the nerve and nerve roots contain very large bundles of juxtaposed, bare axons, reminiscent of Schwann cell-a xon interactions in early development. Within these bundles there are axons large enough to be myelinated. The relationship between the path ologic changes in the muscles and nerves is not clear. The phenotypic abnormalities of these animals resemble those that occur in the sponta neous mouse mutants dystrophia muscularis and myodystrophy. Neverthele ss, the chromosomal position of the transgene integration site, which was mapped by fluorescent in situ hybridization to chromosome 11, indi cates that this disorder represents a new neuromuscular mutation.