Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors

Corina Anastasaki, Anne L. Estep, Richard Marais, Katherine A Rauen, E. Elizabeth Patton

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The Ras/MAPK pathway is critical for human development and plays a central role in the formation and progression of most cancers. Children born with germ-line mutations in BRAF, MEK1 or MEK2 develop cardio-facio-cutaneous (CFC) syndrome, an autosomal dominant syndrome characterized by a distinctive facial appearance, heart defects, skin and hair abnormalities and mental retardation. CFC syndrome mutations in BRAF promote both kinase-activating and kinase-impaired variants. CFC syndrome has a progressive phenotype, and the availability of clinically active inhibitors of the MAPK pathway prompts the important question as to whether such inhibitors might be therapeutically effective in the treatment of CFC syndrome. To study the developmental effects of CFC mutant alleles in vivo, we have expressed a panel of 28 BRAF and MEK alleles in zebrafish embryos to assess the function of human disease alleles and available chemical inhibitors of this pathway. We find that both kinase-activating and kinase-impaired CFC mutant alleles promote the equivalent developmental outcome when expressed during early development and that treatment of CFC-zebrafish embryos with inhibitors of the FGF-MAPK pathway can restore normal early development. Importantly, we find a developmental window in which treatment with a MEK inhibitor can restore the normal early development of the embryo, without the additional, unwanted developmental effects of the drug.

Original languageEnglish (US)
Pages (from-to)2543-2554
Number of pages12
JournalHuman Molecular Genetics
Volume18
Issue number14
DOIs
StatePublished - 2009
Externally publishedYes

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Zebrafish
Phosphotransferases
Alleles
Mitogen-Activated Protein Kinase Kinases
Skin
Embryonic Structures
Skin Abnormalities
Critical Pathways
Germ-Line Mutation
Human Development
Intellectual Disability
Hair
Embryonic Development
Therapeutics
Phenotype
Mutation
Cardiofaciocutaneous syndrome
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. / Anastasaki, Corina; Estep, Anne L.; Marais, Richard; Rauen, Katherine A; Patton, E. Elizabeth.

In: Human Molecular Genetics, Vol. 18, No. 14, 2009, p. 2543-2554.

Research output: Contribution to journalArticle

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