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

• Published in: The Lancet (British edition) Vol. 358; no. 9284; pp. 801 - 807
• Main Authors: Jouvenceau, Anne, Eunson, Louise H, Spauschus, Alexander, Ramesh, Venkataswaran, Zuberi, Sameer M, Kullmann, Dimitri M, Hanna, Michael G
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 08.09.2001; Lancet; Elsevier Limited
• Subjects: Adult; Animal models; Ataxia; Biological and medical sciences; Brain; Brain - metabolism; Brain research; Calcium; Calcium channels; Calcium channels (P/Q-type); Calcium channels (voltage-gated); Calcium Channels - genetics; Calcium Channels, N-Type; Calcium Channels, P-Type; Calcium Channels, Q-Type; Calcium ions; Central nervous system; Chromosome 19; Chromosomes, Human, Pair 19; Data analysis; Epilepsy; Epilepsy, Absence - complications; Epilepsy, Absence - genetics; Gait Ataxia - complications; Gait Ataxia - genetics; Genes; Humans; Identification methods; Kinetics; Male; Medical sciences; Mutants; Mutation; Nervous system involvement in other diseases. Miscellaneous; Neural coding; Neurology; NMR; Nonsense mutation; Nuclear magnetic resonance; Phenotype; Phenotypes; Point Mutation; Pore formation; Rodents; Stop codon; United States > US; Human; Chromosome 19; Nervous system diseases; Epilepsy; Male; Ionic channel; Cerebral disorder; Heterozygosity; Case study; Phenotype; Calcium ion; Gene; Central nervous system disease; Ataxia; Mutation; Neurological disorder; Child; Brain (vertebrata)
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(01)05971-2

The genetic basis of most common forms of human paroxysmal disorders 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 associated with both epilepsy and episodic ataxia type 2 in human beings. We identified an 11-year-old boy with a complex phenotype comprising primary generalised epilepsy, episodic and progressive ataxia, and mild learning difficulties. We sequenced the entire coding region of the gene encoding the voltage-gated P/Q-type Ca2+ channel (CACNA1A) on chromosome 19. We 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. We identified a previously undescribed heterozygous point mutation (C5733T) in CACNA1A. This mutation introduces a premature stop codon (R1820stop) resulting in complete loss of the C terminal region of the pore-forming subunit of this Ca2+ channel. Expression studies provided direct evidence that this mutation impairs Ca2+ channel function. Mutant/wild-type co-expression studies indicated a dominant negative effect. Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca2+ channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models.