title: Impaired FGF signaling contributes to cleft lip and palate.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Riley
authors.forename: M Adela
authors.initials: MA
authors.lastname: Mansilla
authors.forename: Jinghong
authors.initials: J
authors.lastname: Ma
authors.forename: Sandra
authors.initials: S
authors.lastname: Daack-Hirsch
authors.forename: Brion S
authors.initials: BS
authors.lastname: Maher
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Raffensperger
authors.forename: Erilynn T
authors.initials: ET
authors.lastname: Russo
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Vieira
authors.forename: Catherine
authors.initials: C
authors.lastname: Dodé
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002971:Cleft Lip / Q000235:genetics* / Q000378:metabolism*; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D005346:Fibroblast Growth Factors