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Impaired FGF signaling contributes to cleft lip and palate

Riley, BM and Mansilla, MA and Ma, J and Daack-Hirsch, S and Maher, BS and Raffensperger, LM and Russo, ET and Vieira, AR and Dodé, C and Mohammad, M and Marazita, ML and Murray, JC (2007) Impaired FGF signaling contributes to cleft lip and palate. Proceedings of the National Academy of Sciences of the United States of America, 104 (11). 4512 - 4517. ISSN 0027-8424

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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 non-sense 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. © 2007 by The National Academy of Sciences of the USA.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Riley, BM
Mansilla, MA
Ma, J
Daack-Hirsch, S
Maher, BS
Raffensperger, LM
Russo, ET
Vieira, ARarv11@pitt.eduARV11
Dodé, C
Mohammad, M
Marazita, MLmarazita@pitt.eduMARAZITA
Murray, JC
Date: 13 March 2007
Date Type: Publication
Journal or Publication Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 104
Number: 11
Page Range: 4512 - 4517
DOI or Unique Handle: 10.1073/pnas.0607956104
Schools and Programs: School of Dental Medicine > Dental Science
Refereed: Yes
ISSN: 0027-8424
MeSH Headings: Amino Acid Sequence; Animals; Cleft Lip--genetics; Cleft Lip--metabolism; Cleft Palate--genetics; Cleft Palate--metabolism; Female; Fibroblast Growth Factors--genetics; Fibroblast Growth Factors--metabolism; Humans; Male; Models, Molecular; Molecular Sequence Data; Mutation; Pedigree; Polymorphism, Single Nucleotide; Sequence Homology, Amino Acid; Signal Transduction
Other ID: NLM PMC1810508
PubMed Central ID: PMC1810508
PubMed ID: 17360555
Date Deposited: 20 Sep 2012 20:34
Last Modified: 06 Oct 2022 17:39


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