Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Abstract

Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia, Heart Rhythm, http://dx.doi.org/10. 1016/j.hrthm.2015.03.033 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Reduced expression of cardiac ryanodine receptor protects against stress-induced ventricular tachyarrhythmia, but increases the susceptibility to cardiac alternans

“…It has been shown that the severity of CPVT phenotypes in individuals with the same RyR2 mutations (e.g. deletion of exon-3 or G357S) can differ substantially [23,[25][26][27][28]. Although the exact mechanism underlying the phenotypic variability in the same families or in individuals with the same mutations is unknown, our finding suggests that reduced RyR2 protein expression may be one of the many factors that determine the penetrance of CPVT.…”

“…It is possible that some CPVT-linked RyR2 mutations alter not only the gating properties of RyR2, but also its protein expression, which would in turn affect the propensity for CPVT. In support of this view, we have previously shown that deletion of exon-3 and the point mutation G357S markedly reduce the protein expression of RyR2, which may contribute to the incomplete penetrance of CPVT in individuals with these mutations [22][23][24]. Interestingly, Bongianino et al [37] recently employed RNA interference to specifically reduce the protein expression of the RyR2 mutant allele in a CPVT mouse model expressing the RyR2 mutation R4496C.…”

“…Some CPVT-linked RyR2 mutations, such as the deletion of exon-3 and the point mutation G357S, were found to markedly reduce the expression of the RyR2 protein [22][23][24]. Interestingly, the clinical phenotypes and severities of individuals carrying these mutations appear to be highly variable, some of them are even asymptomatic [23,[25][26][27][28]. These observations suggest that reduced RyR2 protein expression may contribute to the incomplete penetrance of CPVT phenotypes.…”

Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2

“…Ultimately, the consequence of the structural alterations to the SPRY region produced by P1124L appears to be a cytosolic loss-of-function, as we determined using 2 complementary assays, [ 3 H] ryanodine binding with recombinant protein and single channel recordings with mouse SR microsomes, and a SR luminal gain-of-function, which we measured in the SCR assay in HEK293 cells. This is a rather distinct phenotype that, to our knowledge, has only been identified in 1 other mutation of variable penetrance linked to CPVT1 (24,35). While our experiments were carried out using Homo P1124L channels, in the Het condition, as in the patient, any phenotype will be the aggregate result of the absolute expression of each allele and the resulting heterogeneous population of channels containing none to 4 mutant subunits.…”

A novel variant in RyR2 causes familiar catecholaminergic polymorphic ventricular tachycardia

“…This has also been recommended in the young boy without the phenotype but carrier of the genetic variant (III.2). This approach is based on our experience with a large family with more than 170 carriers of a pathogenic variant in RyR2 [12]. Current guidelines recommend early genetic testing for clinical management and therapeutic decisions involving family members at any age because CPVT may be presented as SCD as the first manifestation of the disease (even in infants) [5].…”