A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes

• Published in: Scientific reports Vol. 11; no. 1; p. 5243
• Main Authors: Touat-Hamici, Zahia, Blancard, Malorie, Ma, Ruifang, Lin, Lianyun, Iddir, Yasmine, Denjoy, Isabelle, Leenhardt, Antoine, Yuchi, Zhiguang, Guicheney, Pascale
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 04.03.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adult; Age; Aged; Aged, 80 and over; Calcium (intracellular); Calcium Signaling - genetics; Calcium-binding protein; Cardiac arrhythmia; Cardiomyocytes; Cardiovascular disease; Cardiovascular diseases; Conduction; Connexins - genetics; Coronary artery disease; Death, Sudden - epidemiology; Defibrillators; Exome Sequencing; Family medical history; Female; Fibers; Fibrillation; Gap Junction alpha-5 Protein; Genetics; Heart; Heart diseases; HEK293 Cells; Humans; Ischemia; Kinases; Life Sciences; Male; Membrane Proteins - genetics; Metabolism; Middle Aged; Mutation; Myocardial Ischemia - genetics; Myocardial Ischemia - pathology; Patients; Phosphoproteins - genetics; Protein Domains - genetics; Protein Serine-Threonine Kinases - genetics; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine receptors; Syncope; Tachycardia; Torsades de pointes; Torsades de Pointes - complications; Torsades de Pointes - genetics; Torsades de Pointes - pathology; Troponin; Troponin I; Ventricle; Ventricular Fibrillation - genetics; Ventricular Fibrillation - pathology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-84373-9

Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants: p.I784F in the SPRY1 of the ryanodine receptor 2 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca handling in WT and mutant human RYR2 transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca release in response to cytosolic Ca was observed in RyR2-I784F cells. In addition, crystal structures and thermal melting temperatures revealed a conformational change in the I784F-SPRY1 domain compared to the WT-domain. The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions. The presence of several variants affecting Ca handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.