Novel RyR2 Mutation (G3118R) Is Associated With Autosomal Recessive Ventricular Fibrillation and Sudden Death: Clinical, Functional, and Computational Analysis

BACKGROUND: The cardiac ryanodine receptor type 2 (RyR2) is a large homotetramer, located in the sarcoplasmic reticulum (SR), which releases Ca(2+) from the SR during systole. The molecular mechanism underlying Ca(2+) sensing and gating of the RyR2 channel in health and disease is only partially elucidated. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1) is the most prevalent syndrome caused by RyR2 mutations. METHODS AND RESULTS: This study involves investigation of a family with 4 cases of ventricular fibrillation and sudden death and physiological tests in HEK 293 cells and normal mode analysis (NMA) computation. We found 4 clinically affected members who were homozygous for a novel RyR2 mutation, G3118R, whereas their heterozygous relatives are asymptomatic. G3118R is located in the periphery of the protein, far from the mutation hotspot regions. HEK293 cells harboring G3118R mutation inhibited Ca(2+) release in response to increasing doses of caffeine, but decreased the termination threshold for store‐overload‐induced Ca(2+) release, thus increasing the fractional Ca(2+) release in response to increasing extracellular Ca(2+). NMA showed that G3118 affects RyR2 tetramer in a dose‐dependent manner, whereas in the model of homozygous mutant RyR2, the highest entropic values are assigned to the pore and the central regions of the protein. CONCLUSIONS: RyR2 G3118R is related to ventricular fibrillation and sudden death in recessive mode of inheritance and has an effect of gain of function on the protein. Despite a peripheral location, it has an allosteric effect on the stability of central and pore regions in a dose‐effect manner.