Traditionally regarded as a genetic disease of the cardiac sarcomere, hypertrophic cardiomyopathy
(HCM) is the most common inherited cardiovascular disease and a significant cause of sudden cardiac death.
While the most common etiologies of this phenotypically diverse disease lie in a handful of genes encoding
critical contractile myofilament proteins, approximately 50% of patients diagnosed with HCM worldwide do not
host sarcomeric gene mutations. Recently, mutations in genes encoding calcium-sensitive and calciumhandling
proteins have been implicated in the pathogenesis of HCM. Among these are mutations in TNNC1-
encoded cardiac troponin C, PLN-encoded phospholamban, and JPH2-encoded junctophilin 2 which have
each been associated with HCM in multiple studies. In addition, mutations in RYR2-encoded ryanodine
receptor 2, CASQ2-encoded calsequestrin 2, CALR3-encoded calreticulin 3, and SRI-encoded sorcin have
been associated with HCM, although more studies are required to validate initial findings. While a relatively
uncommon cause of HCM, mutations in genes that encode calcium-handling proteins represent an emerging
genetic subset of HCM. Furthermore, these naturally occurring disease-associated mutations have provided
useful molecular tools for uncovering novel mechanisms of disease pathogenesis, increasing our
understanding of basic cardiac physiology, and dissecting important structure-function relationships within
Keywords: Calcium, genetics, hypertrophic cardiomyopathy, junctophilin, mutation, phospholamban, troponin.
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