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Advances in the Genetic Basis and Pathogenesis of Sarcomere Cardiomyopathies

Authors
  • Yotti, Raquel
  • Seidman, Christine E.
  • Seidman, Jonathan G.
Type
Published Article
Journal
Annual Review of Genomics and Human Genetics
Publisher
Annual Reviews
Publication Date
Aug 31, 2019
Volume
20
Pages
129–153
Identifiers
DOI: 10.1146/annurev-genom-083118-015306
Source
Annual Reviews
Keywords
License
Yellow

Abstract

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are common heart muscle disorders that are caused by pathogenic variants in sarcomere protein genes. HCM is characterized by unexplained cardiac hypertrophy (increased chamber wall thickness) that is accompanied by enhanced cardiac contractility and impaired relaxation. DCM is defined as increased ventricular chamber volume with contractile impairment. In this review, we discuss recent analyses that provide new insights into the molecular mechanisms that cause these conditions. HCM studies have uncovered the critical importance of conformational changes that occur during relaxation and enable energy conservation, which are frequently disturbed by HCM mutations. DCM studies have demonstrated the considerable prevalence of truncating variants in titin and have discerned that these variants reduce contractile function by impairing sarcomerogenesis. These new pathophysiologic mechanisms open exciting opportunities to identify new pharmacological targets and develop future cardioprotective strategies.

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