HCN4 and arrhythmias: Insights into base mutations.

In the human sinoatrial node (SAN), HCN4 is the primary subtype among the four HCN (hyperpolarization activated cyclic nucleotide-gated) family subtypes. A tetramer of HCN subunits forms the ion channel conducting the hyperpolarization-activated "funny" current (If), which plays an important regulatory role in maintaining the pacemaker activity of the SAN. With the advancement of detection technologies over the past 20 years, the relationship between base mutations in the HCN4 gene encoding the HCN4 protein and arrhythmias has been continuously elucidated. The expression and kinetic changes of mutated channels were investigated in COS-7, CHO, HEK-293T cells, and Xenopus oocytes, but their functional changes were not elucidated in human myocardial cells. New genome editing methods, such as Base editor and Prime editor, use components of the CRISPR system and other enzymes to directly install single-gene mutation into cellular DNA without causing double-stranded DNA breaks, which reproduce and correct base mutations. In this review, we summarize all base mutations of the HCN4 gene, discuss the clinical characteristics and function of some base mutations, and combine base editors to explore the establishment of disease models and the potential for future gene correction.