An Autosomal Dominant Mutation In Calsequestrin 2 Causes Cpvt Without Changing Protein Levels
BIOPHYSICAL JOURNAL(2019)
Abstract
Calsequestrin-2 (Casq2) is a high capacity, low affinity calcium (Ca) binding protein located in the junctional sarcoplasmic reticulum (SR) of cardiac myocytes. As the major SR Ca buffer, Casq2 interacts with the ryanodine receptor (RyR2), a Ca release channel, to regulate the amount of Ca that is released during the excitation-contraction (EC) coupling cycle, a process that couples electrical activation to mechanical force (i.e. a heartbeat). Alterations in EC coupling can cause both contractile dysfunction and cardiac arrhythmias. Reduction or loss of Casq2 due to mutations causes a severe genetic arrhythmia syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT). Casq2-linked CPVT is usually autosomal-recessive, with mutations resulting in either a severe reduction or complete loss of Casq2 protein. As a result, SR Ca buffering is reduced, which leads to spontaneous Ca release and arrhythmias. In 2016, a genetic analysis conducted in a family that had an autosomal dominant inheritance of CPVT uncovered a novel missense mutation (K180R) within Casq2. This was the first autosomal dominant mutation found in Casq2. It was proposed that this mutation created a dominant negative mutation in Casq2, which would lead to degradation and loss of Casq2. The goal of our study was to generate a heterozygous K180R knock-in mouse model to evaluate the levels Casq2 and test whether the K180R mutation causes CPVT. Our results show that K180R knock-in mice have normal Casq2 protein levels but exhibit CPVT when stressed. This suggests that Casq2-K180R causes CPVT by a different mechanism than previously reported autosomal-recessive Casq2 mutations. Future studies will investigate the ability for Casq2-K180R to regulate RyR2 Ca release channels and how this could alter SR Ca buffering, leading to spontaneous Ca release.
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Key words
autosomal dominant mutation,calsequestrin,cpvt
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