HCN4 – Sinoatrial Node Disorder

Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) is the primary pacemaker channel in human sinoatrial node cells. Loss-of-function variants in HCN4 reduce the inward "funny" current (If), impair diastolic depolarization, and manifest clinically as sinoatrial node disorder (SND). The phenotype ranges from asymptomatic sinus bradycardia to symptomatic chronotropic incompetence and syncope. Both heterozygous truncating and missense variants have been reported, supporting an autosomal-dominant inheritance with dominant-negative or haploinsufficient mechanisms.

Initial candidate-gene screening in a patient with idiopathic SND identified a heterozygous 1-bp deletion, c.1631del (p.Pro544ArgfsTer30), predicting a truncated C-terminus and loss of the cyclic nucleotide-binding domain (PMID:12750403). In a separate family, a 13-nt insertion (c.2783del) causing a truncated HCN4-695X subunit was found in a 45-year-old woman with sinus bradycardia; pedigree analysis confirmed 7 additional affected relatives co-segregating the variant (n=8 carriers vs n=6 unaffected; PMID:20693575). These reports establish heterozygous truncating alleles as recurrent causes of familial SND.

Segregation data include at least 7 additional affected relatives carrying pathogenic HCN4 alleles (PMID:20693575), with multiple unrelated probands harboring deleterious frameshift or missense changes (e.g., D553N; PMID:15123648). The variant spectrum spans frameshift (n=2), nonsense (n=1), and trafficking-defective missense mutations (n=1), each confirmed in independent pedigrees. Recurrent or founder alleles have not been observed, and carrier frequency in population databases remains low.

Functional studies in heterologous systems have consistently demonstrated loss of If due to impaired channel gating, reduced cAMP sensitivity, or defective membrane expression. The D553N missense variant exhibits dominant-negative trafficking defects and markedly decreased current density (PMID:15123648). The HCN4-695X truncation abrogates cAMP responsiveness yet incorporates into the membrane and suppresses wild-type channels in a dominant-negative fashion (PMID:20693575). Additional biophysical analyses corroborate a gating defect mediated by the C-linker region (PMID:23075627).

A common variant, V759I, initially classified as potentially pathogenic, failed to alter channel kinetics, cAMP gating, or cell surface expression and did not segregate with disease in a familial SND pedigree (PMID:33095298). This underscores the necessity of rigorous functional validation to distinguish benign HCN4 polymorphisms from pathogenic alleles.

Collectively, heterozygous HCN4 truncating and select missense variants confer a definitive autosomal-dominant risk for sinoatrial node disorder, supported by co-segregation in ≥8 affected individuals, de novo and familial occurrence, and concordant in vitro loss-of-function assays. Genetic testing for HCN4 variants is clinically useful for diagnosis, risk stratification, and guiding management of bradyarrhythmias. Future studies may explore targeted therapies to restore If or compensate for deficient cAMP-mediated pacemaker regulation.

References

• The Journal of clinical investigation • 2003 • Pacemaker channel dysfunction in a patient with sinus node disease. PMID:12750403
• Circulation: Arrhythmia and Electrophysiology • 2010 • cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control. PMID:20693575
• The Journal of biological chemistry • 2004 • Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. PMID:15123648
• Cellular physiology and biochemistry • 2012 • The HCN4 channel mutation D553N associated with bradycardia has a C-linker mediated gating defect. PMID:23075627
• Pflugers Archiv: European Journal of Physiology • 2020 • Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking. PMID:33095298

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