Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome
- PMID: 16439621
- DOI: 10.1126/science.1124642
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.
Similar articles
-
Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.Methods Enzymol. 2008;438:277-89. doi: 10.1016/S0076-6879(07)38019-1. Methods Enzymol. 2008. PMID: 18413255
-
Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options.Hum Mol Genet. 2008 Feb 1;17(3):419-30. doi: 10.1093/hmg/ddm319. Epub 2007 Nov 2. Hum Mol Genet. 2008. PMID: 17981815
-
Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome.J Med Genet. 2007 Dec;44(12):763-71. doi: 10.1136/jmg.2007.050450. Epub 2007 Aug 17. J Med Genet. 2007. PMID: 17704260 Free PMC article.
-
Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway.Expert Rev Mol Med. 2008 Dec 9;10:e37. doi: 10.1017/S1462399408000902. Expert Rev Mol Med. 2008. PMID: 19063751 Review.
-
[Human development and the RAS/MAPK pathway].Seikagaku. 2007 Jan;79(1):34-8. Seikagaku. 2007. PMID: 17319511 Review. Japanese. No abstract available.
Cited by
-
Cardio-facio-cutaneous syndrome with BRAF gene mutation: A case report and literature review.Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021 Apr 28;46(4):432-437. doi: 10.11817/j.issn.1672-7347.2021.190756. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021. PMID: 33967092 Free PMC article. Review. Chinese, English.
-
The RASopathies.Annu Rev Genomics Hum Genet. 2013;14:355-69. doi: 10.1146/annurev-genom-091212-153523. Epub 2013 Jul 15. Annu Rev Genomics Hum Genet. 2013. PMID: 23875798 Free PMC article. Review.
-
Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling.Mol Cell. 2013 Feb 21;49(4):751-8. doi: 10.1016/j.molcel.2012.12.018. Epub 2013 Jan 24. Mol Cell. 2013. PMID: 23352452 Free PMC article.
-
Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association.Hum Genet. 2023 Mar;142(3):343-350. doi: 10.1007/s00439-022-02497-y. Epub 2022 Dec 5. Hum Genet. 2023. PMID: 36469137 Free PMC article.
-
A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development.Am J Med Genet A. 2012 Sep;158A(9):2106-18. doi: 10.1002/ajmg.a.35449. Epub 2012 Jul 20. Am J Med Genet A. 2012. PMID: 22821884 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous
