title: Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis.
abstract: Familial hypertrophic cardiomyopathy (HCM) has been defined as a disease of the cardiac sarcomere, although sarcomeric protein mutations are not found in one third of cases. We have recently shown that HCM associated with Wolff-Parkinson-White syndrome (WPW) and conduction disease can be caused by mutations in PRKAG2, which encodes the gamma2 subunit of AMPK, an enzyme central to cellular energy homeostasis. AMPK is a heterotrimer composed of one catalytic subunit (alpha) and two regulatory subunits (beta and gamma). Seven known genes encode the subunit isoforms (alpha1, alpha2, beta1, beta2, gamma1, gamma2, gamma3) and all are expressed in the heart. To better understand the role of AMPK mutations in HCM/WPW and other inherited cardiomyophathies, all 7 subunit genes were screened for mutations in a panel of probands: 3 with HCM/WPW, 4 with DCM/WPW, 38 with HCM alone (in whom contractile protein mutations had not been found) and 13 with DCM alone. In total, 73 amplimers were screened in the 58 probands and a number of polymorphisms, including non-conservative substitutions, were identified. However, no further disease-causing mutations were found in any AMPK subunit gene. These results indicate that HCM with WPW is a distinct, but genetically heterogeneous, condition caused by mutations in PRKAG2 and in an unknown gene or genes, not involved in the AMPK complex. Mutations in PRKAG2 appear to specifically cause HCM with WPW and conduction disease, and not other inherited cardiomyopathies. As deleterious alleles were not found in other AMPK subunit isoforms, the mutations affecting PRKAG2 are likely to confer a specific alteration of AMPK function of particular importance in the myocardium.
mesh_terms: D055372:AMP-Activated Protein Kinases; D000483:Alleles; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology*; D002384:Catalysis; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D005091:Exons; D006801:Humans; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics*; D017434:Protein Structure, Tertiary
chemical_list: D018076:DNA, Complementary; D009097:Multienzyme Complexes; D020033:Protein Isoforms; C526181:PRKAA2 protein, human; C526182:PRKAB1 protein, human; C526183:PRKAB2 protein, human; C526222:PRKAG1 protein, human; C526225:PRKAG3 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human