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Noonan, Costello and cardio–facio–cutaneous syndromes: dysregulation of the Ras–MAPK pathway

Published online by Cambridge University Press:  09 December 2008

William E. Tidyman  and
Katherine A. Rauen
William E. Tidyman
Affiliation:
Department of Anatomy, University of CaliforniaSan Francisco, CA, USA.
Katherine A. Rauen*
Affiliation:
Department of Pediatrics, Division of Medical Genetics, University of CaliforniaSan Francisco, CA, USA. UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
*
*Corresponding author: Katherine A. Rauen, UCSF Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, Room S429, Box 0128, San Francisco, CA 94115, USA. Tel: +1 415 514 3513; Fax: +1 415 502 3179; E-mail: [email protected]
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Abstract

A class of developmental disorders caused by dysregulation of the Ras-induced mitogen-activated protein kinase (MAPK) cascade (the Ras–MAPK pathway) has emerged. Three of these disorders – Noonan, Costello and cardio–facio–cutaneous syndromes – have overlapping phenotypic features characterised by distinctive facial dysmorphia, cardiac defects, musculoskeletal and cutaneous abnormalities, and neurocognitive delay. The germline mutations associated with these disorders are in genes that encode proteins of the Ras–MAPK pathway. In vitro studies have determined that the overwhelming majority of these mutations result in increased signal transduction down the pathway, but usually to a lesser degree than somatic mutations in the same genes that are associated with cancer. The Ras–MAPK pathway is essential in the regulation of the cell cycle, differentiation, growth and senescence, so it is not surprising that germline mutations that affect its function have profound effects on development. Here we review the clinical consequences of the known molecular lesions associated with Noonan syndrome, Costello syndrome and cardio–facio–cutaneous syndrome, and explore possible therapeutic modalities for treatment.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e37
Copyright
Copyright © Cambridge University Press 2008

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References

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Further reading, resources and contacts

Clinical genetics reviews on Noonan, Costello and cardio-facio-cutaneous syndrome can be found at GeneTests:

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=noonanGoogle Scholar
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=costelloGoogle Scholar
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cfcGoogle Scholar
http://stke.sciencemag.org/Google Scholar
http://www.signaling-gateway.org/update/Google Scholar
http://www.noonansyndrome.org (Noonan Syndrome Support Group)Google Scholar
http://www.costellokids.com (International Costello Syndrome Support Group)Google Scholar
http://www.cfcsyndrome.org (CFC International)Google Scholar