Recessive POPDC1 Truncation Causes Lethal Short-QT Pattern Arrhythmogenic Cardiomyopathy with Multi-Ion Channel Remodeling and Ankyrin-G Scaffold Disruption

Aims Biallelic variants in Popeye domain containing 1 ( POPDC1 ) classically cause limb-girdle muscular dystrophy, but their impact on cardiac system remains unclear. We investigated the functional consequence of a POPDC1 frameshift variant (c.448delT), first identified in a consanguineous family with arrhythmogenic cardiomyopathy (ACM) and sudden death. Methods and results Comprehensive clinical and genetic evaluation was followed by mechanistic studies in an orthologous Popdc1 knock-in rat model. Functional characterization included biotelemetry and programed electrical stimulation, optical mapping, patch clamp, intracellular Ca 2+ imaging, proteomics, and oxidative stress assays. Homozygous mutants ( Popdc1 fs/fs ) exhibited a shortened QTc interval and high incidence of ventricular tachycardia compared to wild-type ( Popdc1 +/+ ). Urethane anesthesia provoked second-degree AV block in all 10 Popdc1 fs/fs rats but in only 1 of 9 Popdc1 +/+ littermates. Optical mapping demonstrated abbreviated action potentials, slowed conduction velocity, and inducible polymorphic VT. Patch clamp confirmed accelerated repolarization, with upregulated transient outward potassium currents ( I to ) and L-type calcium currents ( I Ca, L ), but downregulated peak sodium currents ( I Na ). Multi-omics and ultrastructural analyses revealed a post-translational collapse of intercalated disc: POPDC1 loss destabilized Ankyrin-G and its membrane-anchored cargo, Nav1.5, coinciding with enhanced Kv4.3 and Cav1.2 protein levels. These disruptions create a convergence of delayed conduction and shortened refractoriness, forming substrate for malignant re-entry. Conclusion We defined a recessive short-QT ACM leading to potentially fatal arrhythmias caused by biallelic POPDC1 truncation driving Ankyrin-G disruption, manifesting as a triad: (1) bradycardia/AV block, (2) accelerated repolarization as short-QT pattern/diffuse T-wave flattening or inversion, and (3) progressive cardiomyopathy and sudden death. What’s new? We define a novel diagnostic triad for recessive short-QT arrhythmogenic cardiomyopathy (rSQT-ACM) in a loss-of-function POPDC1 truncation: (1) early-onset bradyarrhythmia (sinus bradycardia or AV block); (2) a paradoxical short-QT interval with maladaptive rate response/diffuse T-wave flattening or inversion; and (3) progressive cardiomyopathy accompanied accompanied by with SCD. Mechanistically, biallelic POPDC1 truncation induces collapse of the POPDC1-AnkG hub, which triggers a unique “opposing remodeling” phenotype (severe I Na reduction coupled with paradoxical upregulation of Kv4.3-mediated I to ), and established a unified “slow-conduction, short-wavelength” substrate that underpins malignant re-entry. Implications for safety and device therapy: Nav1.5 deficiency indicates that sodium channel blockers may be contraindicated, and early ICD implantation may be preferable to bradycardia pacing. Mechanism-directed treatments: POPDC1’s recessive inheritance and small gene size make it a strong candidate for AAV-mediated gene supplementation aimed at restoring the intercalated disc architecture and ion-channel anchoring. Abstract Figure Graphical Abstract