Biochemical Characterization of Novel Germline BRAF and MEK Mutations in Cardio-Facio-Cutaneous Syndrome

Pablo Rodriguez-Viciana, Katherine A Rauen

Research output: Chapter in Book/Report/Conference proceedingChapter

18 Citations (Scopus)

Abstract

Cardio-facio-cutaneous syndrome (CFC) is a sporadic, complex developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, growth deficiency, hypotonia, and developmental delay. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterogeneous de novo germline mutations in B-Raf mutant proteins, MEK1 and MEK2. Approximately 75% of individuals with CFC have mutations in BRAF. In vitro functional studies demonstrate that many of these mutations confer increase activity upon the mutant protein as compared to the wildtype protein. However, as is seen cancer, some of the B-Raf mutant proteins are kinase impaired. Western blot analyses corroborate kinase assays as determined by mutant proteins phosphorylating downstream effectors MEK and ERK. Approximately 25% of individuals with CFC have mutations in either MEK1 or MEK2 that lead to increased MEK kinase activity as judged by increased phosphorylation of its downstream effector ERK. Unlike BRAF, no somatic mutations have ever been identified in MEK genes. The identification of novel germline BRAF and MEK mutations in CFC will help understand the pathophysiology of this syndrome. Furthermore, it will also provide insight to the normal function of B-Raf and MEK, and contribute to the knowledge of the role of the MAPK pathway in cancer. Since the MAPK pathway has been studied intensively in the context of cancer, numerous therapeutics that specifically target this pathway may merit investigation in this population of patients.

Original languageEnglish (US)
Title of host publicationSmall GTPases in Disease, Part A
Pages277-289
Number of pages13
Volume438
DOIs
StatePublished - 2008
Externally publishedYes

Publication series

NameMethods in Enzymology
Volume438
ISSN (Print)00766879

Fingerprint

Mitogen-Activated Protein Kinase Kinases
Mutant Proteins
Mitogen-Activated Protein Kinases
Mutation
MAP Kinase Kinase Kinases
Phosphorylation
Neoplasms
Muscle Hypotonia
Protein Kinases
Germ-Line Mutation
Assays
Phosphotransferases
Genes
Defects
Western Blotting
Cardiofaciocutaneous syndrome
Growth
Proteins
Population

ASJC Scopus subject areas

  • Biochemistry

Cite this

Rodriguez-Viciana, P., & Rauen, K. A. (2008). Biochemical Characterization of Novel Germline BRAF and MEK Mutations in Cardio-Facio-Cutaneous Syndrome. In Small GTPases in Disease, Part A (Vol. 438, pp. 277-289). (Methods in Enzymology; Vol. 438). https://doi.org/10.1016/S0076-6879(07)38019-1

Biochemical Characterization of Novel Germline BRAF and MEK Mutations in Cardio-Facio-Cutaneous Syndrome. / Rodriguez-Viciana, Pablo; Rauen, Katherine A.

Small GTPases in Disease, Part A. Vol. 438 2008. p. 277-289 (Methods in Enzymology; Vol. 438).

Research output: Chapter in Book/Report/Conference proceedingChapter

Rodriguez-Viciana, P & Rauen, KA 2008, Biochemical Characterization of Novel Germline BRAF and MEK Mutations in Cardio-Facio-Cutaneous Syndrome. in Small GTPases in Disease, Part A. vol. 438, Methods in Enzymology, vol. 438, pp. 277-289. https://doi.org/10.1016/S0076-6879(07)38019-1
Rodriguez-Viciana P, Rauen KA. Biochemical Characterization of Novel Germline BRAF and MEK Mutations in Cardio-Facio-Cutaneous Syndrome. In Small GTPases in Disease, Part A. Vol. 438. 2008. p. 277-289. (Methods in Enzymology). https://doi.org/10.1016/S0076-6879(07)38019-1
Rodriguez-Viciana, Pablo ; Rauen, Katherine A. / Biochemical Characterization of Novel Germline BRAF and MEK Mutations in Cardio-Facio-Cutaneous Syndrome. Small GTPases in Disease, Part A. Vol. 438 2008. pp. 277-289 (Methods in Enzymology).
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