Abstract for presentation at 11th International Congress of Human Genetics

Germline mutations in HRAS proto-oncogene cause Costello syndrome

  • Yoko Aoki, Department of Medical Genetics, Tohoku University School of Medicine, Japan
  • Tetsuya Niihori, Department of Medical Genetics, Tohoku University School of Medicine, Japan
  • Hiroshi Kawame, Division of Medical Genetics, Nagano Children’s Hospital, Japan
  • Kenji Kurosawa, Division of Medical Genetics, Kanagawa Children’s Medical Center, Japan
  • Hirofumi Ohashi, Division of Medical Genetics, Saitama Children’s Medical Center, Japan
  • Mirella Filocamo, Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, IRCCS G.Gaslini, Italy
  • Shigeo Kure, Department of Medical Genetics, Tohoku University School of Medicine, Japan
  • Yoichi Matsubara, Department of Medical Genetics, Tohoku University School of Medicine, Japan

    • Costello syndrome is a rare, multiple congenital anomaly syndrome characterized by coarse face, mental retardation, cardiomyopathy and predisposition to tumors. The molecular basis of the disease has been unknown. Mutations in tyrosine phosphatase SHP-2 (PTPN11) have been identified in approximately 40% of patients with Noonan syndrome (1), which phenotypically overlaps with Costello syndrome. We hypothesized that the causative gene(s) for Costello syndrome and Noonan syndrome without PTPN11 mutations is a functionally upstream or downstream molecule(s) of SHP-2 in the RAS-RAF-ERK pathway. We sequenced the entire coding regions of the four RAS genes (K-RAS, H-RAS, N-RAS and E-RAS) in genomic DNA from 13 individuals with Costello syndrome and 28 individuals with PTPN11-negative Noonan syndrome. We identified four heterozygous de novo mutations of H-RAS (G12V, G12A, G12S and G13D) in 12 of 13 affected individuals, all of which have been previously reported as somatic and “oncogenic” mutations in various tumors (2). Fibroblasts established from patients were hypersensitive to growth factor stimulation as compared with control fibroblasts. Only a mutant allele was expressed in the ganglioneuroblastoma tissue surgically isolated from an individual with Costello syndrome despite the biallelic expression in her fibroblasts. Our observations strongly suggest that germline mutations in H-RAS perturb human development and are likely to increase susceptibility to tumors.
    (1) Tartaglia, M. & Gelb, B.D. Eur J Med Genet 48, 81-96 (2005).
    (2) Aoki, Y. et al. Nat Genet 37, 1038-40 (2005).

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