title: Mutation analysis of the hyperpolarization-activated cyclic nucleotide-gated channels HCN1 and HCN2 in idiopathic generalized epilepsy.
abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN1-4) channels play an important role in the regulation of neuronal rhythmicity. In the present study we describe the mutation analysis of HCN1 and HCN2 in 84 unrelated patients with idiopathic generalized epilepsy (IGE). Several functional variants were identified including the amino acid substitution R527Q in HCN2 exon 5. HCN2 channels containing the R527Q variant demonstrated a trend towards a decreased slope of the conductance-voltage relation. We also identified a variant in the splice donor site of HCN2 exon 5 that results in the formation of a cryptic splice donor. In HCN1, the amino acid substitution A881T was identified in one sporadic IGE patient but was not observed in 510 controls. Seven variants were examined further in a case-control association study consisting of a larger cohort of IGE patients. Further studies are warranted to more clearly establish the contribution of HCN1 and HCN2 dysfunction to the genetic variance of common IGE syndromes.
authors.affiliation: Department of Human Genetics, Emory University, 615 Michael Street, Whitehead Building, Suite 301, Atlanta, GA 30322, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.forename: Kimberley B
authors.initials: KB
authors.lastname: Craven
authors.forename: Anne
authors.initials: A
authors.lastname: Hempelmann
authors.forename: Andrew
authors.initials: A
authors.lastname: Escayg
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D004829:Epilepsy, Generalized / Q000145:classification / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005973:Glutamine / Q000235:genetics; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics*; D014162:Transfection / Q000379:methods; D014982:Xenopus laevis
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578665:HCN1 protein, human; C578710:HCN2 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D005973:Glutamine; D001120:Arginine