HRAS mutants identified in Costello syndrome patients can induce cellular senescence: Possible implications for the pathogenesis of Costello syndrome

Tetsuya Niihori, Yoko Aoki, Nobuhiko Okamoto, Kenji Kurosawa, Hirofumi Ohashi, Seiji Mizuno, Hiroshi Kawame, Johji Inazawa, Toshihiro Ohura, Hiroshi Arai, Shin Nabatame, Kiyoshi Kikuchi, Yoshikazu Kuroki, Masaru Miura, Toju Tanaka, Akira Ohtake, Isaku Omori, Kenji Ihara, Hiroyo Mabe, Kyoko WatanabeShinichi Niijima, Erika Okano, Hironao Numabe, Yoichi Matsubara

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.

Original languageEnglish
Pages (from-to)707-715
Number of pages9
JournalJournal of Human Genetics
Volume56
Issue number10
DOIs
Publication statusPublished - 2011 Oct

Keywords

  • Costello syndrome
  • HRAS
  • RAS/MAPK
  • phenotype-genotype
  • senescence

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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