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Originally published in Science Express on 26 January 2006
Science 3 March 2006:
Vol. 311. no. 5765, pp. 1287 - 1290
DOI: 10.1126/science.1124642
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Reports

Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome

Pablo Rodriguez-Viciana,1* Osamu Tetsu,1,2* William E. Tidyman,3 Anne L. Estep,1 Brenda A. Conger,6 Molly Santa Cruz,6 Frank McCormick,1,4 Katherine A. Rauen1,5{dagger}

Cardio-facio-cutaneous (CFC) syndrome is a sporadic developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, and developmental delay. We demonstrate that heterogeneous de novo missense mutations in three genes within the mitogen-activated protein kinase (MAPK) pathway cause CFC syndrome. The majority of cases (18 out of 23) are caused by mutations in BRAF, a gene frequently mutated in cancer. Of the 11 mutations identified, two result in amino acid substitutions that occur in tumors, but most are unique and suggest previously unknown mechanisms of B-Raf activation. Furthermore, three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf. Our findings highlight the involvement of the MAPK pathway in human development and will provide a molecular diagnosis of CFC syndrome.

1 Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, CA 94115, USA.
2 Department of Pathology, University of California, San Francisco, CA 94115, USA.
3 Department of Anatomy, University of California, San Francisco, CA 94115, USA.
4 Department of Microbiology and Immunology, University of California, San Francisco, CA 94115, USA.
5 Department of Pediatrics, University of California, San Francisco, CA 94115, USA.
6 CFC International, Vestal, NY 13850, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: rauen{at}cc.ucsf.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)