Journal Article

Impaired FGF signaling contributes to cleft lip and palate

Daack-Hirsch, Sandra, Vieira, Alexandre R, Mohammadi, Moosa, Mansilla, M. Adela, Raffensperger, Lisa M, Dodé, Catherine, Murray, Jeffrey C, Ma, Jinghong, Maher, Brion S, Riley, Bridget M, Russo, Erilynn T, Marazita, Mary L

2007

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Amino Acid Sequence / Amino acids / Animals / Biological Sciences / Birth defects / Cell growth / Chickens / Cleft Lip - genetics / Cleft Lip - metabolism / Cleft lip and palate / Cleft palate / Cleft Palate - genetics / Cleft Palate - metabolism / congenital abnormalities / Environmental factors / Female / fibroblast growth factor receptor 1 / fibroblast growth factor receptor 2 / fibroblast growth factor receptor 3 / Fibroblast Growth Factors - genetics / Fibroblast Growth Factors - metabolism / Genes / Genetic mutation / Genetics / genotyping / Humans / Male / missense mutation / Models, Molecular / Molecular Sequence Data / Mouth / Mutation / nonsense mutation / palate / Pedigree / Phenotypes / Polymorphism, Single Nucleotide / protein structure / proteins / Rats / Receptors / Sequence Homology, Amino Acid / Sequencing / Signal Transduction / single nucleotide polymorphism / Stem cells / Structural analysis