title: Myocardial KRAS(G12D) expression does not cause cardiomyopathy in mice.
abstract: OBJECTIVE
  Germ-line mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) pathway cause developmental disorders called RASopathies. Hypertrophic cardiomyopathy (HCM) is the most common myocardial pathology and a leading cause of death in RASopathy patients. KRAS mutations are found in Noonan and cardio-facio-cutaneous syndromes. KRAS mutations, unlike mutations of RAF1 and HRAS, are rarely associated with HCM. This has been attributed to the fact that germ-line KRAS mutations cause only a moderate up-regulation of the MAPK pathway. Highly bioactive KRAS mutations have been hypothesized to cause severe cardiomyopathy incompatible with life. The aim of this study was to define the impact of KRAS(G12D) expression in the heart.
  
  
  RESULTS
  To generate mice with endogenous cardiomyocyte-specific KRAS(G12D) expression (cKRAS(G12D) mice), we bred mice with a Cre-inducible allele expressing KRAS(G12D) from its endogenous promoter (Kras2(LSL)) to mice expressing Cre under control of the cardiomyocyte-specific α-myosin heavy chain promoter (αMHC-Cre). cKRAS(G12D) mice showed high levels of myocardial ERK and AKT signalling. However, surprisingly, cKRAS(G12D) mice were born in Mendelian ratios, appeared healthy, and had normal function, size, and histology of the heart.
  
  
  CONCLUSIONS
  Mice with cardiomyocyte-specific KRAS(G12D) expression do not develop heart pathology. These results challenge the view that the level of MAPK activation correlates with the severity of HCM in RASopathies and suggests that MAPK-independent strategies may be of interest in the development of new treatments for these syndromes.
authors.affiliation: Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 425, S-41390 Gothenburg, Sweden.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Dalin
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zou
authors.forename: Margareta
authors.initials: M
authors.lastname: Scharin-Täng
authors.forename: Roghaiyeh
authors.initials: R
authors.lastname: Safari
authors.forename: Christin
authors.initials: C
authors.lastname: Karlsson
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
mesh_terms: D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009203:Myocardial Infarction; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014463:Ultrasonography; D016277:Ventricular Function, Left; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C045073:Cre recombinase; D019426:Integrases; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Cardio-facio-cutaneous syndrome; Cardiomyopathy; KRAS; Noonan syndrome; RASopathies