Impaired FGF signaling contributes to cleft lip and palate
Journal, Book or Conference Title
Proceedings of the National Academy of Sciences of the United States of America
NLM Title Abbreviation
Proc Natl Acad Sci U S A
Nonsyndromic cleft lip and palate (NS CLP) is a complex birth defect resulting from a combination of genetic and environmental factors. Several members of the FGF and FGFR families are expressed during craniofacial development and can rarely harbor mutations that result in human clefting syndromes. We hypothesized that disruptions in this pathway might also contribute to NS CLP. We sequenced the coding regions and performed association testing on 12 genes (FGFR1, FGFR2, FGFR3, FGF2, FGF3, FGF4, FGF7, FGF8, FGF9, FGF10, FGF18, and NUDT6) and used protein structure analyses to predict the function of amino acid variants. Seven likely disease-causing mutations were identified, including: one nonsense mutation (R609X) in FGFR1, a de novo missense mutation (D73H) in FGF8, and other missense variants in FGFR1, FGFR2, and FGFR3. Structural analysis of FGFR1, FGFR2, and FGF8 variants suggests that these mutations would impair the function of the proteins, albeit through different mechanisms. Genotyping of SNPs in the genes found associations between NS CLP and SNPs in FGF3, FGF7, FGF10, FGF18, and FGFR1. The data suggest that the FGF signaling pathway may contribute to as much as 3-5% of NS CLP and will be a consideration in the clinical management of CLP.
Amino Acid Sequence, Animals, Cleft Lip/genetics/metabolism, Cleft Palate/genetics/metabolism, Female, Fibroblast Growth Factors/genetics/metabolism, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Polymorphism, Single Nucleotide, Sequence Homology, Amino Acid, Signal Transduction
Published Article/Book Citation
The definitive version was published in Proceedings of the National Academy of Sciences of the United States of America, 104:11 (2007) pp.4512-4517. DOI:10.1073/pnas.0607956104.
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