Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse.
Ca2+ channel beta subunits regulate voltage-dependent calcium currents through direct interaction with alpha 1 subunits. The beta- and alpha 1-binding motifs are conserved, and all beta subunits can stimulate current amplitude, voltage dependence, and kinetics when coexpressed with various alpha 1 subunits. We used a positional candidate approach to determine that the ataxia and seizures in the lethargic (lh) mouse arise from mutation of the beta-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 alpha 1-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.
Burgess
D L
DL
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
Jones
J M
JM
Meisler
M H
MH
Noebels
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics*; D004251:DNA Transposable Elements; D005091:Exons; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009928:Organ Specificity / Q000235:genetics; D012326:RNA Splicing; D012333:RNA, Messenger / Q000096:biosynthesis; D012640:Seizures / Q000235:genetics* / Q000378:metabolism*
D015220:Calcium Channels; D004251:DNA Transposable Elements; D012333:RNA, Messenger