Human Molecular Genetics, 2001, Vol. 10, No. 17 1819-1827
© 2001 Oxford University Press
Pathological and genetic analysis of the degenerating muscle (dmu) mouse: a new allele of Scn8a
1Ottawa Health Research Institute, Ottawa, ON K1H 8L6, Canada, and The University of Ottawa Center for Neuromuscular Disease, 2Department of Cellular and Molecular Medicine and 3Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada and 4Centre de recherche Guy-Bernier de l’Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada
Here, we describe a novel spontaneous autosomal recessive mutation in the mouse that is characterized by skeletal and cardiac muscle degeneration. We have named this mutant degenerating muscle (dmu). At birth, mutant mice are indistinguishable from their normal littermates. Thereafter, the disease progresses rapidly and a phenotype is first observed at 
11 days after birth; the dmu mice are weak and have great difficulty in moving. The principal cause of the lack of mobility is muscle atrophy and wasting in the hindquarters. Affected mice die at or around the time of weaning of unknown causes. Histopathological observations and ultrastructural analysis revealed muscle degeneration in both skeletal and cardiac muscle, but no abnormalities in sciatic nerves. Using linkage analysis, we have mapped the dmu locus to the distal portion of mouse chromosome 15 in a region syntenic to human chromosome 12q13. Interestingly, scapuloperoneal muscular dystrophy (SPMD) in humans has been linked to this region. SPMD patients with associated cardiomyopathy have also been described in the past. Initial analysis of candidate genes on mouse chromosome 15 reveal that although intact transcripts for Scn8a, the gene encoding the sodium channel 8a subunit, are present in dmu mice, their levels are dramatically reduced. Furthermore, genetic complementation crosses between dmu and med (mutation in Scn8a) mice revealed that they are allelic. Our results suggest that at least a portion of the dmu phenotype is caused by a down-regulation of Scn8a, making dmu a new allele of Scn8a.
+ To whom correspondence should be addressed at: Ottawa Health Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. Tel: +1 613 737 8707; Fax: +1 613 737 8803; Email: rkothary@ohri.ca
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