Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel

Background The genetic basis of most common forms of human paroxysmal disor ders of the central nervous system, such as epilepsy, remains unidentified. Several animal models of absence epilepsy, commonly accompanied by ataxia, are caused by mutations in the brain P/Q-type voltage-gated calcium (Ca2+) channel. We aimed to determine whether the P/Q-type Ca2+ channel is associ ated with both epilepsy and episodic ataxia type 2 in human beings. Methods We identified an 11-year-old boy with a complex phenotype comprisin g primary generalised epilepsy, episodic and progressive ataxia, and mild l earning difficulties. We sequenced the entire coding region of the gene enc oding the voltage-gated P/Q-type Ca2+ channel (CACNA1A) on chromosome 19. W e then introduced the newly identified heterozygous mutation into the full- length rabbit cDNA and did detailed electrophysiological expression studies of mutant and wild type Ca2+ channels. Findings We identified a previously undescribed heterozygous point mutation (C5733T) in CACNA1A. This mutation introduces a premature stop codon (RI82 0stop) resulting in complete loss of the C terminal region of the pore-form ing subunit of this Ca 2 channel. Expression studies provided direct eviden ce that this mutation impairs Ca2+ channel function. Mutant/wild-type co-ex pression studies indicated a dominant negative effect. Interpretation Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca 2 channel. The phenotype in this patie nt has striking parallels with the mouse absence epilepsy models.