Calcium Channel β4 (CACNB4): Human Ortholog of the Mouse Epilepsy Genelethargic

Abstract

The mouse neurological mutant lethargic (lh) is characterized by ataxia, focal myoclonus, and absence epilepsy due to a loss-of-function mutation in the β4 subunit of the voltage-gated calcium channel. To evaluate the role of this channel subunit in human neurological disease, we determined the chromosomal location and intron/exon structure of the humanCACNB4gene. The 1560-bp open reading frame of theCACNB4cDNA predicts a 58-kDa protein with an amino acid sequence that is 99% identical to the rat protein. The 13 coding exons ofCACNB4span >55 kb of genomic DNA. Human cerebellar RNA contains one majorCACNB4transcript that is 9 kb in length. Expression ofCACNB4was detected in cerebellum, kidney, testis, retina, lymphoblasts, and circulating lymphocytes. Retinal transcripts were localized byin situhybridization to ganglion cells and the inner nuclear layer. Analysis of the GeneBridge 4 radiation hybrid mapping panel localizedCACNB4to position 791 cR on human chromosome 2, in a conserved linkage group on human 2q22–q31 and mouse chromosome 2. We localizedCACNB4to the 1.3-Mb YAC clone 952F10 in Whitehead contig WC861, along with the polymorphic markersD2S2236andD2S2299.The chromosomal linkage of three of the four β subunit genes to homeobox gene clusters associates the evolutionary origin of the β gene family with the events that generated the four HOX clusters early in vertebrate evolution.