title: Novel brain expression of ClC-1 chloride channels and enrichment of CLCN1 variants in epilepsy.
abstract: OBJECTIVE
  To explore the potential contribution of genetic variation in voltage-gated chloride channels to epilepsy, we analyzed CLCN family (CLCN1-7) gene variant profiles in individuals with complex idiopathic epilepsy syndromes and determined the expression of these channels in human and murine brain.
  
  
  METHODS
  We used parallel exomic sequencing of 237 ion channel subunit genes to screen individuals with a clinical diagnosis of idiopathic epilepsy and evaluate the distribution of missense variants in CLCN genes in cases and controls. We examined regional expression of CLCN1 in human and mouse brain using reverse transcriptase PCR, in situ hybridization, and Western immunoblotting.
  
  
  RESULTS
  We found that in 152 individuals with sporadic epilepsy of unknown origin, 96.7% had at least one missense variant in the CLCN genes compared with 28.2% of 139 controls. Nonsynonymous single nucleotide polymorphisms in the "skeletal" chloride channel gene CLCN1 and in CLCN2, a putative human epilepsy gene, were detected in threefold excess in cases relative to controls. Among these, we report a novel de novo CLCN1 truncation mutation in a patient with pharmacoresistant generalized seizures and a dystonic writer's cramp without evidence of variants in other channel genes linked to epilepsy. Molecular localization revealed the unexpectedly widespread presence of CLCN1 mRNA transcripts and the ClC-1 subunit protein in human and murine brain, previously believed absent in neurons.
  
  
  CONCLUSIONS
  Our findings support a possible comorbid contribution of the "skeletal" chloride channel ClC-1 to the regulation of brain excitability and the need for further elucidation of the roles of CLCN genes in neuronal network excitability disorders.
authors: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors: Tim T
authors: TT
authors: Chen
authors: Tara L
authors: TL
authors: Klassen
authors: Alica M
authors: AM
authors: Goldman
authors: Carla
authors: C
authors: Marini
authors: Renzo
authors: R
authors: Guerrini
authors: Jeffrey L
authors: JL
authors: Noebels
mesh_terms: D000328:Adult; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology*; D018118:Chloride Channels / Q000096:biosynthesis* / Q000235:genetics; D015331:Cohort Studies; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D012333:RNA, Messenger