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HCN4 gene

hyperpolarization activated cyclic nucleotide gated potassium channel 4

Normal Function

The HCN4 gene provides instructions for making a channel that transports positively charged atoms (ions) into heart muscle cells. This channel is located primarily in the sino-atrial (SA) node, which is an area of specialized cells in the heart that functions as a natural pacemaker. The HCN4 channel allows potassium and sodium ions to flow into cells of the SA node. This ion flow is often called the "pacemaker current" because it generates electrical impulses that start each heartbeat and is involved in maintaining a regular heart rhythm.

Health Conditions Related to Genetic Changes

Sick sinus syndrome

At least five mutations in the HCN4 gene have been identified in people with sick sinus syndrome, a heart condition that affects the function of the SA node. Most of these mutations change single protein building blocks (amino acids) in the HCN4 channel. In some cases, fewer of the altered channels reach the cell membrane, where they are needed to transport ions. In other cases, the channel is in the right place but has an abnormal structure that changes how ions flow through it. All of the mutations reduce the overall flow of ions into cells of the SA node, preventing it from creating the electrical signals that control the heartbeat. These changes increase the risk of an abnormally slow heartbeat (bradycardia), which can cause dizziness, light-headedness, fainting (syncope), and related symptoms. HCN4 gene mutations have also been found in people who have a slow heartbeat without any other symptoms (asymptomatic bradycardia).

More About This Health Condition

Brugada syndrome

MedlinePlus Genetics provides information about Brugada syndrome

More About This Health Condition

Left ventricular noncompaction

MedlinePlus Genetics provides information about Left ventricular noncompaction

More About This Health Condition

Other Names for This Gene

  • hyperpolarization activated cyclic nucleotide-gated cation channel 4
  • hyperpolarization activated cyclic nucleotide-gated potassium channel 4
  • potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
  • SSS2

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Gene and Variant Databases


  • Baruscotti M, Bottelli G, Milanesi R, DiFrancesco JC, DiFrancesco D. HCN-related channelopathies. Pflugers Arch. 2010 Jul;460(2):405-15. doi: 10.1007/s00424-010-0810-8. Epub 2010 Mar 8. Citation on PubMed
  • Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med. 2006 Jan 12;354(2):151-7. doi: 10.1056/NEJMoa052475. Erratum In: N Engl J Med. 2006 Jun 8;354(23):2520. Citation on PubMed
  • Netter MF, Zuzarte M, Schlichthorl G, Klocker N, Decher N. The HCN4 channel mutation D553N associated with bradycardia has a C-linker mediated gating defect. Cell Physiol Biochem. 2012;30(5):1227-40. doi: 10.1159/000343314. Epub 2012 Oct 15. Citation on PubMed
  • Nof E, Luria D, Brass D, Marek D, Lahat H, Reznik-Wolf H, Pras E, Dascal N, Eldar M, Glikson M. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation. 2007 Jul 31;116(5):463-70. doi: 10.1161/CIRCULATIONAHA.107.706887. Epub 2007 Jul 23. Citation on PubMed
  • Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet. 2009 Feb;54(2):115-21. doi: 10.1038/jhg.2008.16. Epub 2009 Jan 23. Citation on PubMed
  • Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesato Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem. 2004 Jun 25;279(26):27194-8. doi: 10.1074/jbc.M311953200. Epub 2004 Apr 30. Citation on PubMed

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