title: Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.
abstract: 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.
authors.affiliation: Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, CA 94115, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Rodriguez-Viciana
authors.forename: Osamu
authors.initials: O
authors.lastname: Tetsu
authors.forename: William E
authors.initials: WE
authors.lastname: Tidyman
authors.forename: Anne L
authors.initials: AL
authors.lastname: Estep
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Conger
authors.forename: Molly Santa
authors.initials: MS
authors.lastname: Cruz
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018095:Germ-Line Mutation; D006130:Growth Disorders / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D007223:Infant; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012868:Skin Abnormalities / Q000235:genetics; D013577:Syndrome; D014162:Transfection
chemical_list: C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human