A Titin Missense Variant Causes Atrial Fibrillation

Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes such asTTNhave also been implicated in AF pathogenesis partly by the development of an atrial myopathy, but the underlying mechanisms are poorly understood. WhileTTNtruncating variants (TTNtvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear. We report that rareTTNmvs are associated with adverse clinical outcomes in AF patients and we have identified a mechanism by which aTTNmv (T32756I) causes AF. Modeling theTTN-T32756I variant using human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) revealed that the mutant cells display aberrant contractility, increased activity of a cardiac potassium channel (KCNQ1, Kv7.1), and dysregulated calcium homeostasis without compromising the sarcomeric integrity of the atrial cardiomyocytes. We also show that a titin-binding protein, the Four-and-a-Half Lim domains 2 (FHL2), has increased binding with KCNQ1 and its modulatory subunit KCNE1 in theTTN-T32756I-iPSC-aCMs, enhancing the slow delayed rectifier potassium current (I_ks). Suppression of FHL2 in mutant iPSC-aCMs normalized theI_ks, supporting FHL2 as anI_ksmodulator. Our findings demonstrate that a single amino acid change in titin not only affects function but also causes ion channel remodeling and AF. These findings emphasize the need for high-throughput screening to evaluate the pathogenicity ofTTNmvs and establish a mechanistic link between titin, potassium ion channels, and sarcomeric proteins that may represent a novel therapeutic target.