In vivo severity ranking of Ras pathway mutations associated with developmental disorders.

TitleIn vivo severity ranking of Ras pathway mutations associated with developmental disorders.
Publication TypeJournal Article
Year of Publication2017
AuthorsJindal, GA, Goyal, Y, Yamaya, K, Futran, AS, Kountouridis, I, Balgobin, CA, Schüpbach, T, Burdine, RD, Shvartsman, SY
JournalProc Natl Acad Sci U S A
Date Published2017 01 17
KeywordsAnimals, Animals, Genetically Modified, Developmental Disabilities, Dose-Response Relationship, Drug, Drosophila melanogaster, Drosophila Proteins, Humans, MAP Kinase Kinase 1, MAP Kinase Signaling System, Mutation, Phenotype, Protein Kinase Inhibitors, ras Proteins, Zebrafish, Zebrafish Proteins

<p>Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale. Using this assay, we assessed 16 mutations reported in MEK1, a MAPK kinase, and provide a robust ranking of these mutations. We find that mutations found in cancer are more severe than those found in both RASopathies and cancer, which, in turn, are generally more severe than those found only in RASopathies. Moreover, this rank is conserved in other zebrafish embryonic assays and Drosophila-specific embryonic and adult assays, suggesting that our ranking reflects the intrinsic property of the mutant molecule. Furthermore, this rank is predictive of the drug dose needed to correct the defects. This assay can be readily used to test the strengths of existing and newly found mutations in MEK1 and other pathway components, providing the first step in the development of rational guidelines for patient-specific diagnostics and treatment of RASopathies.</p>

Alternate JournalProc Natl Acad Sci U S A
PubMed ID28049852
PubMed Central IDPMC5255624
Grant ListR01 GM077620 / GM / NIGMS NIH HHS / United States
R01 GM086537 / GM / NIGMS NIH HHS / United States
R01 HD048584 / HD / NICHD NIH HHS / United States