Genetic analysis of hyperpolarization-activated cyclic nucleotide-gated cation channels in sudden unexpected death in epilepsy cases

Brain Pathol. 2011 Nov;21(6):692-8. doi: 10.1111/j.1750-3639.2011.00500.x. Epub 2011 Aug 16.


Sudden unexpected death in epilepsy (SUDEP) is the most common epilepsy-related cause of death, yet the cause is unknown. Our previous studies suggest a role for arrhythmia-related ion channel genes in the pathogenesis of SUDEP. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN1-4) channels are ion channels involved in generating spontaneous rhythmic activity in cardiac pacemaker and neuronal cells. This study sought to determine the role of pathogenic DNA variants in the HCN1-4 genes in a large SUDEP cohort collected from 1993 to 2009. Post-mortem DNA samples were amplified and analyzed for each HCN exon. Genetic analysis in 48 SUDEP cases (age range 12-82 years) identified six novel and three previously reported nonsynonymous (amino acid changing) variants in HCN1 (n = 1), HCN2 (n = 2), HCN3 (n = 2) and HCN4 (n = 4). The Phe738Cys and Pro802Ser variants in HCN2, and Gly973Arg in HCN4 were absent in control alleles and affecting highly conserved residues in the carboxyl-cytoplasmic tail region. Our results support a pathogenic link between the heart and brain in SUDEP, mediated by the HCN neuro-cardiac ion channel genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Base Sequence
  • Child
  • Cyclic Nucleotide-Gated Cation Channels / genetics*
  • Death, Sudden / etiology*
  • Epilepsy / complications
  • Epilepsy / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / genetics*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Muscle Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Potassium Channels / genetics*
  • Young Adult


  • Cyclic Nucleotide-Gated Cation Channels
  • HCN1 protein, human
  • HCN2 protein, human
  • HCN3 protein, human
  • HCN4 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Muscle Proteins
  • Potassium Channels