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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Abnormalities, Multiple / genetics*
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Adolescent
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Adult
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Amino Acid Substitution
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Child
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Child, Preschool
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Craniofacial Abnormalities / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Germ-Line Mutation*
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Growth Disorders / genetics
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Heart Defects, Congenital / genetics
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Humans
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Infant
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MAP Kinase Kinase 1 / genetics
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MAP Kinase Kinase 2 / genetics
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MAP Kinase Kinase Kinases / metabolism
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MAP Kinase Signaling System
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Male
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Mutation, Missense
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Phosphorylation
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Proto-Oncogene Proteins B-raf / genetics
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Skin Abnormalities / genetics
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Syndrome
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Transfection
Substances
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MAP2K2 protein, human
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human