title: Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants.
abstract: OBJECTIVE
  The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures.
  
  
  METHODS
  Exons 3 to 35 of CACNA1H were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single-stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single-stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by site-directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired.
  
  
  RESULTS
  More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current.
  
  
  CONCLUSIONS
  Variants in CACNA1H that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an individual's susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants; therefore, CACNA1H would not be easily identified as a susceptibility gene by a genome-wide case-control study seeking a statistical association.
authors: Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide South Australia, Australia. sarah.heron@cywhs.sa.gov.au
authors: Sarah E
authors: SE
authors: Heron
authors: Houman
authors: H
authors: Khosravani
authors: Diego
authors: D
authors: Varela
authors: Chris
authors: C
authors: Bladen
authors: Tristiana C
authors: TC
authors: Williams
authors: Michelle R
authors: MR
authors: Newman
authors: Ingrid E
authors: IE
authors: Scheffer
authors: Samuel F
authors: SF
authors: Berkovic
authors: John C
authors: JC
authors: Mulley
authors: Gerald W
authors: GW
authors: Zamponi
mesh_terms: D000595:Amino Acid Sequence; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004594:Electrophysiology; D004829:Epilepsy, Generalized / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D014162:Transfection
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type