Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate disease'

The mouse neurological mutant 'motor endplate disease' (med) is characterized by early onset progressive paralysis of the hind limbs, severe muscle atrophy, degeneration of Purkinje cells and juvenile lethality. We have isolated a voltage-gated sodium channel gene, Scn8a, from the flanking region of a transgene-induced allele of med. Scn8a is expressed in brain and spinal cord but not in skeletal muscle or heart, and encodes a predicted protein of 1,732 amino acids. An intragenic deletion at the transgene insertion site results in loss of expression. Scn8a is closely related to other sodium channel alpha subunits, with greatest similarity to a brain transcript from the pufferfish Fugu rubripes. The human homologue, SCN8A, maps to chromosome 12q13 and is a candidate gene for inherited neurodegenerative disease.