Certain CASQ2 missense variants exhibit a dominant mode of inheritance due to their structural location, indicating a need to clinically screen individuals carrying these variants for CPVT.
Select CASQ2 missense variants may exert dominant-negative effects in models; extends mechanistic insights but leaves clinical screening implications open.
BACKGROUND: -CPVT was sought through an international multicenter collaboration. METHODS: missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. RESULTS: missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. CONCLUSIONS: variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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Ng et al. (2020) studied this question.
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