title: HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome.
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.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan. tniihori@med.tohoku.ac.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Seiji
authors.initials: S
authors.lastname: Mizuno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawame
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ohura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Shin
authors.initials: S
authors.lastname: Nabatame
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kuroki
authors.forename: Masaru
authors.initials: M
authors.lastname: Miura
authors.forename: Toju
authors.initials: T
authors.lastname: Tanaka
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.forename: Isaku
authors.initials: I
authors.lastname: Omori
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Mabe
authors.forename: Kyoko
authors.initials: K
authors.lastname: Watanabe
authors.forename: Shinichi
authors.initials: S
authors.lastname: Niijima
authors.forename: Erika
authors.initials: E
authors.lastname: Okano
authors.forename: Hironao
authors.initials: H
authors.lastname: Numabe
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D056685:Costello Syndrome / Q000235:genetics* / Q000503:physiopathology*; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: D003062:Codon; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)