title: Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.
abstract: BACKGROUND
  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 (Ca(2+)) channel. We aimed to determine whether the P/Q-type Ca(2+) channel is associated with both epilepsy and episodic ataxia type 2 in human beings.
  
  
  METHODS
  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 Ca(2+) 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 Ca(2+) channels.
  
  
  RESULTS
  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 Ca(2+) channel. Expression studies provided direct evidence that this mutation impairs Ca(2+) channel function. Mutant/wild-type co-expression studies indicated a dominant negative effect.
  
  
  CONCLUSIONS
  Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca(2+) channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models.
authors.affiliation: University Department of Clinical Neurology, Institute of Neurology, University College London, Queen Square, WC1N 3BG, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Jouvenceau
authors.forename: L H
authors.initials: LH
authors.lastname: Eunson
authors.forename: A
authors.initials: A
authors.lastname: Spauschus
authors.forename: V
authors.initials: V
authors.lastname: Ramesh
authors.forename: S M
authors.initials: SM
authors.lastname: Zuberi
authors.forename: D M
authors.initials: DM
authors.lastname: Kullmann
authors.forename: M G
authors.initials: MG
authors.lastname: Hanna
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics*; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002888:Chromosomes, Human, Pair 19; D004832:Epilepsy, Absence / Q000150:complications / Q000235:genetics*; D020234:Gait Ataxia / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D010641:Phenotype; D017354:Point Mutation
chemical_list: D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; C105656:CACNA1A protein, human