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
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 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
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID ![](/images/orcid_id_24x24.png) |
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Riley, BM | | | | Mansilla, MA | | | | Ma, J | | | | Daack-Hirsch, S | | | | Maher, BS | | | | Raffensperger, LM | | | | Russo, ET | | | | Vieira, AR | arv11@pitt.edu | ARV11 | | Dodé, C | | | | Mohammad, M | | | | Marazita, ML | marazita@pitt.edu | MARAZITA | | Murray, JC | | | |
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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 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/14231 |
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