Germline KRAS Mutations Cause Aberrant Biochemical and Physical Properties Leading to Developmental Disorders

Institute of Biochemistry and Molecular Biology II, Heinrich-Heine University, Düsseldorf, Germany.
Human Mutation (Impact Factor: 5.05). 01/2011; 32(1):33-43. DOI: 10.1002/humu.21377
Source: PubMed

ABSTRACT The KRAS gene is the most common locus for somatic gain-of-function mutations in human cancer. Germline KRAS mutations were shown recently to be associated with developmental disorders, including Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFCS), and Costello syndrome (CS). The molecular basis of this broad phenotypic variability has in part remained elusive so far. Here, we comprehensively analyzed the biochemical and structural features of ten germline KRAS mutations using physical and cellular biochemistry. According to their distinct biochemical and structural alterations, the mutants can be grouped into five distinct classes, four of which markedly differ from RAS oncoproteins. Investigated functional alterations comprise the enhancement of intrinsic and guanine nucleotide exchange factor (GEF) catalyzed nucleotide exchange, which is alternatively accompanied by an impaired GTPase-activating protein (GAP) stimulated GTP hydrolysis, an overall loss of functional properties, and a deficiency in effector interaction. In conclusion, our data underscore the important role of RAS in the pathogenesis of the group of related disorders including NS, CFCS, and CS, and provide clues to the high phenotypic variability of patients with germline KRAS mutations.

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Available from: Martin Zenker, Jul 29, 2015
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    • "The cancer mutations were extracted from the OMIM database , which lists all mutations even if not confirmed to be diseasecausing [in cancer often > 200 proteins are mutated and not all are expected to be disease-causing (Vogelstein et al, 2013)]. To exclude possible cancer passenger mutations, we generated a 'gold set' of RASopathy and cancer mutations by including only those mutations that have been already studied experimentally, and for which there is evidence of their transforming potential, or for which sustained increased kinase activity has been demonstrated (Wan et al, 2004; Gremer et al, 2011) (Supplementary Table S2). Using this gold set, the FoldX energy values for germline and cancer mutants separate "
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    ABSTRACT: The Ras/MAPK syndromes (‘RASopathies’) are a class of developmental disorders caused by germline mutations in 15 genes encoding proteins of the Ras/mitogen-activated protein kinase (MAPK) pathway frequently involved in cancer. Little is known about the molecular mechanisms underlying the differences in mutations of the same protein causing either cancer or RASopathies. Here, we shed light on 956 RASopathy and cancer missense mutations by combining protein network data with mutational analyses based on 3D structures. Using the protein design algorithm FoldX, we predict that most of the missense mutations with destabilising energies are in structural regions that control the activation of proteins, and only a few are predicted to compromise protein folding. We find a trend that energy changes are higher for cancer compared to RASopathy mutations. Through network modelling, we show that partly compensatory mutations in RASopathies result in only minor downstream pathway deregulation. In summary, we suggest that quantitative rather than qualitative network differences determine the phenotypic outcome of RASopathy compared to cancer mutations.
    Molecular Systems Biology 05/2014; 10(5). DOI:10.1002/msb.20145092 · 14.10 Impact Factor
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    • "The diversity of functional consequences of KRAS mutations in developmental diseases are paralleled by a wide phenotypic spectrum and tempting to assume a causal relation between certain genotypes and phenotypes. There is indeed a tendency towards an association of more severe phenotypes (CFC/CS) with mutations that proved to have stronger effects on ERK1/2 phosphorylation [Gremer et al., 2011]. In contrast, patients harboring the mutations p.V14I, p.P34L, p.D153V have less severe physical and mental handicaps and are more commonly classified as having NS, the less severe form among this group of developmental disorders [Aoki et al., 2008]. "
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