Beyond the cardiac myofilament: Hypertrophic cardiomyopathy-associated mutations in genes that encode calcium-handling proteins

A. P. Landstrom, Michael John Ackerman

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 these proteins.

Original languageEnglish (US)
Pages (from-to)507-518
Number of pages12
JournalCurrent Molecular Medicine
Volume12
Issue number5
StatePublished - Jun 2012

Fingerprint

Myofibrils
Hypertrophic Cardiomyopathy
Genes
Calcium
Mutation
Gene encoding
Proteins
Calsequestrin
Calreticulin
Troponin C
Contractile Proteins
Ryanodine Receptor Calcium Release Channel
Physiology
Sarcomeres
Inborn Genetic Diseases
Sudden Cardiac Death
Cardiovascular Diseases

Keywords

  • Calcium
  • genetics
  • hypertrophic cardiomyopathy
  • junctophilin
  • mutation
  • phospholamban
  • troponin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Molecular Medicine

Cite this

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abstract = "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 these proteins.",
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