Mutations in the gamma2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis.

作者：Edward M. Blair, Charles S Redwood, Houman Ashrafian, Sandra Marisa Oliveira, John Broxholme, Bronwyn A. Kerr, Anthony P. Salmon, Ingegerd Östman‐Smith, Hugh C Watkins · 发表于：Journal of Medical Genetics · 年份：2001 · 被引用次数：124 · 研究领域：Cardiomyopathy and Myosin Studies、Cardiovascular Function and Risk Factors、Metabolism, Diabetes, and Cancer

Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the γ2 subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff–