Dystonia associated with mutation of the neuronal sodium channel Scn8a andidentification of the modifier locus Scnm1 on mouse chromosome 3

The mouse mutant med(J) contains a splice site mutation in the neuronal sod ium channel Scn8a that results in a very low level of expression. On a C57B L/6J genetic background, med(J) homozygotes exhibit progressive paralysis a nd juvenile lethality. The C3H genetic background has an ameliorating effec t, producing viable adults with a novel dystonic phenotype. The dystonic mi ce exhibit movement-induced, sustained abnormal postures of the trunk and l imbs. A dominant modifier locus responsible for the difference between stra ins was mapped to a 4.5 +/- 1.3 cM interval on mouse chromosome 3. Our find ings establish a role for ion channels in dystonia and demonstrate the impa ct of genetic background on its severity and progression. This new model su ggests that SCN8A on chromosome 12q13 and SCNM1 on chromosome 1p21-1q21 may contribute to human inherited dystonia.