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.fibroblast growth factor ͉ fibroblast growth factor receptor ͉ single-nucleotide polymorphism ͉ cleft palate

Studies of genes in the FGF signaling pathway and oral clefts with or without dental anomalies

“…Our results partially corroborate the association data presented by Riley et al [2007] in which several genes (FGF3, FGF7, FGF10, FGF18, and FGFR1) demonstrated a trend for association with nonsyndromic cleft lip and palate. In addition, the diversity in the binding specificity of FGF receptors for FGFs clearly can lead to a large combinatorial set of possible interactions.…”

“…Mutations in FGFR1 cause autosomal dominant Kallmann syndrome, which includes clefts in 30% of the cases and tooth agenesis in 7% [Dodé et al, 2003]. Sequencing of the coding region of genes in the FGF signaling pathway in nonsyndromic cleft cases revealed that missense and nonsense mutations in FGF genes might contribute to approximately 3% of nonsyndromic cleft lip and palate [Riley et al, 2007].…”

“…The SNPs used in this study were chosen from previous studies where associations with oral clefts [Riley et al, 2007] and breast cancer [Easton et al, 2007;Hunter et al, 2007] were described. Details of the studied polymorphisms are shown in Table I.…”

“…rs1219648 FGFR2 10q26 Hunter et al, 2007 rs4631909 FGF3 11q13 Riley et al, 2007 rs4980700 FGF3 11q13 Riley et al, 2007 rs2413958 FGF7 11q13 Riley et al, 2007 …”

MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis

“…For instance, Hh signaling is crucial for palatogenesis in humans and zebrafish 3,4,7 . Zebrafish and amniotes also share expression patterns of palatogenic genes such as Shh 4,8 , Fgf8 4,9,10 and Pdgf receptor alpha (Pdgfra) [11][12][13] .In mouse, the Pdgf family consists of four soluble ligands, Pdgfa, Pdgfb, Pdgfc, and Pdgfd as well as two receptor tyrosine kinases, Pdgfra and Pdgfrb 14 . Pdgf signaling regulates a myriad of biological processes as demonstrated by analyses of mouse Pdgf ligand and receptor mutants 14 .…”