HCN4 and arrhythmias: Insights into base mutations

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Channelopathies

Background:

• HCN4 is the primary hyperpolarization activated cyclic nucleotide-gated (HCN) channel in the human sinoatrial node (SAN).
• The "funny" current (If) mediated by HCN4 channels is crucial for SAN pacemaker activity.
• HCN4 gene mutations are increasingly linked to cardiac arrhythmias.

Purpose of the Study:

• To review all identified base mutations in the HCN4 gene.
• To discuss the clinical characteristics and functional consequences of specific HCN4 mutations.
• To explore the potential of base editing technologies for disease modeling and gene correction.

Main Methods:

• Literature review of HCN4 gene mutations and associated arrhythmias.
• Analysis of studies investigating mutated HCN4 channel expression and kinetics in heterologous systems.
• Discussion of novel genome editing tools like Base and Prime editors for targeted gene modification.

Main Results:

• Numerous base mutations in the HCN4 gene have been identified and associated with various arrhythmias.
• Previous studies characterized functional changes in cell lines and oocytes, but not in human myocardial cells.
• Base editors offer precise gene editing without double-stranded DNA breaks, enabling mutation reproduction and correction.

Conclusions:

• HCN4 gene mutations are significant contributors to cardiac arrhythmias.
• Base editing technologies present a promising avenue for establishing accurate disease models and developing gene correction therapies for HCN4-related channelopathies.