Mutation of the Ca2+ Channel β Subunit Gene Cchb4 Is Associated with Ataxia and Seizures in the Lethargic (lh) Mouse

AbstractCa2+ channel β subunits regulate voltage-dependent calcium currents through direct interaction with α1 subunits. The β- and α1-binding motifs are conserved, and all β subunits can stimulate current amplitude, voltage dependence, and kinetics when coexpressed with various α1 subunits. We used a positional candidate approach to determine that the ataxia and seizures in the lethargic (lh) mouse arise from mutation of the β-subunit gene Cchb4 on mouse chromosome 2. A four-nucleotide insertion into a splice donor site results in exon skipping, translational frameshift, and protein truncation with loss of the α1-binding site. The lethargic phenotype is the first example of a mammalian neurological disease caused by an inherited defect in a non-pore-forming subunit of a voltage-gated ion channel