Regulation of calcium flux in the heart is a key process that affects cardiac 
excitability and contractility. Degenerative diseases, such as coronary artery 
disease, have long been recognized to alter the physiology of intracellular 
calcium regulation, leading to contractile dysfunction or arrhythmias. Since the 
discovery of the first gene mutation associated with catecholaminergic 
polymorphic ventricular tachycardia (CPVT) in 2001, a new area of interest in 
this field has emerged--the genetic abnormalities of key components of the 
calcium regulatory system. Such anomalies cause a variety of genetic diseases 
characterized by the development of life-threatening arrhythmias in young 
individuals. In this Review, we provide an overview of the structural 
organization and the function of calcium-handling proteins and describe the 
mechanisms by which mutations determine the clinical phenotype. Firstly, we 
discuss mutations in the genes encoding the ryanodine receptor 2 (RYR2) and 
calsequestrin 2 (CASQ2). These proteins are pivotal to the regulation of calcium 
release from the sarcoplasmic reticulum, and mutations can cause CPVT. Secondly, 
we review defects in genes encoding proteins that form the voltage-dependent 
L-type calcium channel, which regulates calcium entry into myocytes. Mutations 
in these genes cause various phenotypes, including Timothy syndrome, Brugada 
syndrome, and early repolarization syndrome. The identification of mutations 
associated with 'calcium-handling diseases' has led to an improved understanding 
of the role of calcium in cardiac physiology.