title: RAS signaling pathway mutations and hypertrophic cardiomyopathy: getting into and out of the thick of it.
abstract: In this issue of the JCI, Wu et al. and Marin et al. describe two new mouse models of inherited disorders of the RAS/MAPK signal transduction pathway that display hypertrophic cardiomyopathy (HCM); the model from the former paper was from a gain-of-function Raf1 mutation, and the model from the latter paper was from a protein tyrosine phosphatase, non-receptor type 11 (Ptpn11) mutated allele encoding Shp2 with impaired catalytic function. The two groups show that HCM arises from increased signaling through Erk1/2 and the mTor complex 1, respectively, and that those cardiac issues can be prevented or reversed with small-molecule therapies inhibiting the appropriate pathway. Aside from being the first studies of treatment for Noonan syndrome and related disorders in a mammalian system, these papers provide important insights into the role of RAS signaling in cardiac hypertrophy and suggest the complexity in developing meaningful therapy for individuals with these RASopathies.
authors.affiliation: Child Health and Development Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. bruce.gelb@mssm.edu
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D000483:Alleles; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism*; D002384:Catalysis; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D018631:ras Proteins