Pathological and genetic analysis of the degenerating muscle (dmu) mouse: a new allele of Scn8a

Here, we describe a novel spontaneous autosomal recessive mutation in the m ouse 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 p rogresses rapidly and a phenotype is first observed at similar to 11 days a fter 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 th e hindquarters. Affected mice die at or around the time of weaning of unkno wn causes. Histopathological observations and ultrastructural analysis reve aled muscle degeneration in both skeletal and cardiac muscle, but no abnorm alities in sciatic nerves. Using linkage analysis, we have mapped the dmu l ocus to the distal portion of mouse chromosome 15 in a region syntenic to h uman chromosome 12q13. Interestingly, scapuloperoneal muscular dystrophy (S PMD) in humans has been linked to this region. SPMD patients with associate d cardiomyopathy have also been described in the past. Initial analysis of candidate genes on mouse chromosome 15 reveal that although intact transcri pts for Scn8a, the gene encoding the sodium channel 8a subunit, are present in dmu mice, their levels are dramatically reduced. Furthermore, genetic c omplementation crosses between dmu and med (mutation in Scn8a) mice reveale d that they are allellic. Our results suggest that at least a portion of th e dmu phenotype is caused by a down-regulation of Scn8a, making dmu a new a llelle of Scn8a.