Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energycompromise in disease pathogenesis

Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a gen etic model of cardiac hypertrophy and sudden cardiac death. HCM has been de fined as a disease of the cardiac sarcomere, but mutations in the known con tractile protein disease genes are not found in up to one-third of cases. F urther, 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 muta tions appear to result in inefficient use of ATP, suggesting that an inabil ity to maintain normal ATP levels may be the central abnormality. To test t his hypothesis we have examined candidate genes involved in energy homeosta sis in the heart. We now describe mutations in PRKAG2, encoding the gamma ( 2) subunit of AMP-activated protein kinase (AMPK), in two families with sev ere HCM and aberrant conduction from atria to ventricles in some affected i ndividuals (pre-excitation or Wolff-Parkinson-White syndrome). The mutation s, one missense and one in-frame single codon insertion, occur in highly co nserved regions, Because AMPK provides a central sensing mechanism that pro tects cells from exhaustion of ATP supplies, we propose that these data sub stantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM, This conclusion should radically redirect thinking about this diso rder and also, by establishing energy depletion as a cause of myocardial dy sfunction, should be relevant to the acquired forms of heart muscle disease that HCM models.