Yulia Einav
Holon Institute of Technology, Israel
Title: The novel suppression of function mutation in the cardiac RyR2 channel presents an allosteric dose-dependent effect mecchanism
Biography
Biography: Yulia Einav
Abstract
The cardiac ryanodine receptor RyR2 is a calcium release channel present in the sarcoplasmic reticulum, which plays a major role in regulation of Ca2+ homeostasis in the heart. We discovered a novel RyR2 missense mutation, G3118R, with recessive co-segregation, in a large family presenting with cardiac arrest and ventricular fibrillation phenotype. Interestingly, and unlike the other clinically relevant mutations in this gene, which are dominantly inherited, the clinically affected individuals in this family are homozygous for the mutation, whereas the heterozygous family members are almost unaffected. Moreover, the mechanism by which this mutation determines this unusual clinical phenotype is unknown. The aims of this study were to perform functional and structural analysis of G3118R RyR2 in order to investigate the mechanism of this mutation's pathogenicity. We inserted the mutation into HEK293 cells and performed functional studies, including measurements of changes in intracellular Ca2+ levels and the monitoring of the endoplasmic reticulum Ca2+ dynamics. G3118R causes suppression of function of the channel, which is by far less described mechanism caused by most RyR2 mutations. Next, we used a computational model to study the changes in the stability and the flexibility of RyR2 protein. We found that G3118R, a peripheral mutation located in a region, whose function is unknown, causes a major allosteric effect on the channel pore region of two out of the four RyR2 monomers, and that this effect accumulates in a dose-dependent manner.