Autosomal recessive neuromuscular disorder in a transgenic line of mice

• DOI: 10.1523/jneurosci.14-01-00198.1994
• Publication Date: 2018-04-02T14:45:21Z
• Authors: D Kelly; K Chancellor; A Milatovich; U Francke; K Suzuki; B Popko
• Keywords: 0301 basic medicine; Transcription, Genetic; Homozygote; Genes, Recessive; Mice, Transgenic; Myelin Basic Protein; Neuromuscular Diseases; Sciatic Nerve; Mice; Mutagenesis, Insertional; 03 medical and health sciences; Phenotype; Genes; Genes, Regulator; Mutation; Animals; RNA, Messenger

We have generated a line of transgenic mice that when homozygous for the transgene develop a severe, adult-onset neuromuscular disorder. This mutation is likely the result of the insertional inactivation of an endogenous gene by the transgene integration. The mutant mice have a gait abnormality with stiffened and/or splayed hind legs, and adopt a hunched posture with some exhibiting kyphosis of the thoracic spine. These symptoms progress gradually to severe motor dysfunction. Pathologic changes were found in skeletal muscle and peripheral nerve of the mutant animals. In young mice the muscles from both upper and lower extremities show necrosis and phagocytosis. In older mice, regeneration with muscle fiber splitting, internally located nuclei, and variable fiber size are conspicuous features. Interactions between Schwann cells and axons also appear disrupted in these animals. Although many peripheral axons are well myelinated, the nerve and nerve roots contain very large bundles of juxtaposed, bare axons, reminiscent of Schwann cell-axon interactions in early development. Within these bundles there are axons large enough to be myelinated. The relationship between the pathologic changes in the muscles and nerves is not clear. The phenotypic abnormalities of these animals resemble those that occur in the spontaneous mouse mutants dystrophia muscularis and myodystrophy. Nevertheless, the chromosomal position of the transgene integration site, which was mapped by fluorescent in situ hybridization to chromosome 11, indicates that this disorder represents a new neuromuscular mutation.