Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 11, Pages 4512-4517Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0607956104
Keywords
fibroblast growth factor; fibroblast growth factor receptor; single-nucleoticle polymorphism; cleft palate
Categories
Funding
- NIDCR NIH HHS [R37 DE008559-18, DE 16215, DE 13686, P50 DE016215-01, R01 DE008559, R01 DE015197-04, R01 DE016148, DE 08559, R01 DE013686, R01 DE015197, R37 DE008559, P50 DE016215] Funding Source: Medline
- NIEHS NIH HHS [ES 10876, R01 ES010876, R01 ES010876-05] Funding Source: Medline
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Nonsyndromic cleft lip and palate (NIS 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 FGIF signaling pathway may contribute to as much as 3-5% of NS CLP and will be a consideration in the clinical management of CLP.
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