Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome by Rodriguez-Viciana Pablo, Tetsu Osamu, Tidyman William E, Estep Anne L, Conger Brenda A, Cruz Molly Santa, McCormick Frank, Rauen Katherine A in Science (New York, N.Y.) (2006).

[PMID: 16439621] PubMed


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.

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