The RAS/MAPK syndromes: Novel roles of the RAS pathway in human genetic disorders

Yoko Aoki, Tetsuya Niihori, Yoko Narumi, Shigeo Kure, Yoichi Matsubara

Research output: Contribution to journalReview articlepeer-review

263 Citations (Scopus)

Abstract

The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes. html).

Original languageEnglish
Pages (from-to)992-1006
Number of pages15
JournalHuman mutation
Volume29
Issue number8
DOIs
Publication statusPublished - 2008 Aug 1

Keywords

  • BRAF
  • CFC syndrome
  • Costello syndrome
  • HRAS
  • KRAS
  • MAP2K1
  • MAP2K2
  • MAPK
  • Noonan syndrome
  • Oncogene
  • PTPN11
  • RAS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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