Phylogenetic and biochemical analysis of calsequestrin structure and association of its variants with cardiac disorders

Calsequestrin is among the most abundant proteins in muscle sarcoplasmic reticulum and displays a high capacity but a low affinity for Ca(2+) binding. In mammals, calsequestrin is encoded by two genes, CASQ1 and CASQ2, which are expressed almost exclusively in skeletal and cardiac muscles, respectively. Phylogenetic analysis indicates that calsequestrin is an ancient gene in metazoans, and that the duplication of the ancestral calsequestrin gene took place after the emergence of the lancelet. CASQ2 gene variants associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in humans are positively correlated with a high degree of evolutionary conservation across all calsequestrin homologues. The mutations are distributed in diverse locations of the calsequestrin protein and impart functional diversity but remarkably manifest in a similar phenotype in humans.