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

Abstract : 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 Ca2+ handling in WT and mutant human RYR2 transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca2+ release in response to cytosolic Ca2+ 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 Ca2+ handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.
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Submitted on : Monday, March 8, 2021 - 4:36:05 PM
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Zahia Touat-Hamici, Malorie Blancard, Ruifang Ma, Lianyun Lin, Yasmine Iddir, et al.. A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes. Scientific Reports, Nature Publishing Group, 2021, 11 (1), pp.5243. ⟨10.1038/s41598-021-84373-9⟩. ⟨hal-03162735⟩

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