BPS2026 – FAM189A2 deficiency promotes atrial fibrillation through ito current enhancement

Cardiomyopathies are a set of heterogeneous myocardial disorders, and can cause premature sudden cardiac death (SCD) in the young. This burden is exacerbated by the incomplete understanding of their underlying mechanisms, which limits the efficacy of available therapeutic interventions. For this reason, cardiovascular diseases remain a major focus of genetic research to uncover novel genes implicated in their pathogenesis. Recently, the FAM189A2 gene has emerged as a potential contributor to cardiac arrythmias, such as atrial fibrillation (AF), a variant present more often in patients with AF. Although its precise role is not fully elucidated, FAM189A2 is thought to act as a cofactor in ubiquitination and may be involved in protein trafficking to the cell surface and ion channel regulation. In this study, we investigated the role of FAM189A2 in a cardiac context using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). A FAM189A2 knock-out (KO) model was generated to replicate loss-of-function conditions. Electrophysiological characterization via patch-clamp revealed a significant shortening of the action potential (AP) duration in KO hiPSC-CMs compared to their isogenic controls. Additionally, a marked increase in transient outward potassium currents (Ito) was observed, associated with the Kv1.4 channel. Transient re-expression of the wild-type long isoform of FAM189A2 in KO hiPSC-CMs restored AP duration and Ito currents to levels comparable to those in control hiPSC-CMs. Extensive electrophysiological studies in HEK cells demonstrated isoform-specific regulation by FAM189A2 of Kv1.4, Kv4.3 and Kv1.5 potassium channels. Finally, we examined the impact of the novel mutant variant of FAM189A2, FAM189A2/L105R, recently associated with AF, in KO hiPSC-CMs. Our findings confirm that this variant induces a loss-of-function phenotype. These results highlight the critical role of FAM189A2 in regulating cardiac potassium channels and shortening AP and suggest its involvement in the molecular mechanisms underlying AF.