Document Detail


The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders.
MedLine Citation:
PMID:  18470943     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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).
Authors:
Yoko Aoki; Tetsuya Niihori; Yoko Narumi; Shigeo Kure; Yoichi Matsubara
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Human mutation     Volume:  29     ISSN:  1098-1004     ISO Abbreviation:  Hum. Mutat.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-04     Completed Date:  2008-10-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9215429     Medline TA:  Hum Mutat     Country:  United States    
Other Details:
Languages:  eng     Pagination:  992-1006     Citation Subset:  IM    
Affiliation:
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan. aokiy@mail.tains.tohoku.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Animals
Genetic Diseases, Inborn / metabolism*
Humans
MAP Kinase Signaling System*
Syndrome
ras Proteins / genetics*
Chemical
Reg. No./Substance:
EC 3.6.5.2/ras Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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