Mutation in S6 domain of HCN4 channel in patient with suspected Brugada syndrome modifies channel function

Pflugers Arch. 2016 Oct;468(10):1663-71. doi: 10.1007/s00424-016-1870-1. Epub 2016 Aug 23.

Abstract

Diseases such as the sick sinus and the Brugada syndrome are cardiac abnormalities, which can be caused by a number of genetic aberrances. Among them are mutations in HCN4, a gene, which encodes the hyperpolarization-activated, cyclic nucleotide-gated ion channel 4; this pacemaker channel is responsible for the spontaneous activity of the sinoatrial node. The present genetic screening of patients with suspected or diagnosed Brugada or sick sinus syndrome identified in 1 out of 62 samples the novel mutation V492F. It is located in a highly conserved site of hyperpolarization-activated cyclic nucleotide-gated (HCN)4 channel downstream of the filter at the start of the last transmembrane domain S6. Functional expression of mutant channels in HEK293 cells uncovered a profoundly reduced channel function but no appreciable impact on channel synthesis and trafficking compared to the wild type. The inward rectifying HCN4 current could be partially rescued by an expression of heteromeric channels comprising wt and mutant monomers. These heteromeric channels were responsive to cAMP but they required a more negative voltage for activation and they exhibited a lower current density than the wt channel. This suggests a dominant negative effect of the mutation in patients, which carry this heterozygous mutation. Such a modulation of HCN4 activity could be the cause of the diagnosed cardiac abnormality.

Keywords: Channelopathy; HCN pace making; Sick sinus/Brugada syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Brugada Syndrome / diagnosis
  • Brugada Syndrome / genetics*
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Mutation, Missense*
  • Potassium Channels / genetics*
  • Potassium Channels / metabolism
  • Protein Domains
  • Protein Multimerization
  • Protein Transport

Substances

  • HCN4 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Muscle Proteins
  • Potassium Channels