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Submitted on January 5, 2006
Accepted on January 19, 2006
Germline Mutations in Genes within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome
Pablo Rodriguez-Viciana 1, Osamu Tetsu 2, William E. Tidyman 3, Anne L. Estep 1, Brenda A. Conger 4, Molly Santa Cruz 4, Frank McCormick 5, Katherine A. Rauen 6*
1 Comprehensive Cancer Center and Cancer Research Institute 2 Comprehensive Cancer Center and Cancer Research Institute; Department of Pathology 3 Department of Anatomy 4 CFC International, Vestal, NY 13850, USA. 5 Comprehensive Cancer Center and Cancer Research Institute; Department of Microbiology and Immunology 6 Comprehensive Cancer Center and Cancer Research Institute; Department of Pediatrics, University of California, University of California, San Francisco, CA 94115, USA.
* To whom correspondence should be addressed.
Katherine A. Rauen , E-mail: rauen{at}cc.ucsf.edu
Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmentaldisorder involving characteristic craniofacial features, cardiacdefects, ectodermal abnormalities and developmental delay. Wedemonstrate that heterogeneous de novo missense mutations inthree genes within the mitogen-activated protein kinase (MAPK)pathway cause CFC syndrome. The majority of cases (18 out of23) are caused by mutations in BRAF, a gene frequently mutatedin cancer. Of the 11 mutations identified, two result in aminoacid substitutions that occur in tumors, but most are uniqueand suggest novel mechanisms of B-Raf activation. Furthermore,three of five individuals without BRAF mutations had missensemutations in either MEK1 or MEK2, downstream effectors of B-Raf.Our findings highlight the involvement of the MAPK pathway inhuman development and will provide a molecular diagnosis ofCFC syndrome.
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