Impaired FGF signaling contributes to cleft lip and palate

Bridget M. Riley, M. Adela Mansilla, Jinghong Ma, Sandra Daack-Hirsch, Brion Maher, Lisa M. Raffensperger, Erilynn T. Russo, Alexandre R. Vieira, Catherine Dodé, Moosa Mohammad, Mary L. Marazita, Jeffrey C. Murray

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4512-4517
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number11
DOIs
StatePublished - Mar 13 2007
Externally publishedYes

Fingerprint

Cleft Lip
Cleft Palate
Mutation
Single Nucleotide Polymorphism
Fibroblast Growth Factor 2
Missense Mutation
Genes
Proteins
Amino Acids
Orofacial Cleft 1

Keywords

  • Cleft palate
  • Fibroblast growth factor
  • Fibroblast growth factor receptor
  • Single-nucleotide polymorphism

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Riley, B. M., Mansilla, M. A., Ma, J., Daack-Hirsch, S., Maher, B., Raffensperger, L. M., ... Murray, J. C. (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. https://doi.org/10.1073/pnas.0607956104

Impaired FGF signaling contributes to cleft lip and palate. / Riley, Bridget M.; Mansilla, M. Adela; Ma, Jinghong; Daack-Hirsch, Sandra; Maher, Brion; Raffensperger, Lisa M.; Russo, Erilynn T.; Vieira, Alexandre R.; Dodé, Catherine; Mohammad, Moosa; Marazita, Mary L.; Murray, Jeffrey C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 11, 13.03.2007, p. 4512-4517.

Research output: Contribution to journalArticle

Riley, BM, Mansilla, MA, Ma, J, Daack-Hirsch, S, Maher, B, Raffensperger, LM, Russo, ET, Vieira, AR, Dodé, C, Mohammad, M, Marazita, ML & 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, vol. 104, no. 11, pp. 4512-4517. https://doi.org/10.1073/pnas.0607956104
Riley, Bridget M. ; Mansilla, M. Adela ; Ma, Jinghong ; Daack-Hirsch, Sandra ; Maher, Brion ; Raffensperger, Lisa M. ; Russo, Erilynn T. ; Vieira, Alexandre R. ; Dodé, Catherine ; Mohammad, Moosa ; Marazita, Mary L. ; Murray, Jeffrey C. / Impaired FGF signaling contributes to cleft lip and palate. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 11. pp. 4512-4517.
@article{c511fb4354e44ce99df8bed06e1802b3,
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 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.",
keywords = "Cleft palate, Fibroblast growth factor, Fibroblast growth factor receptor, Single-nucleotide polymorphism",
author = "Riley, {Bridget M.} and Mansilla, {M. Adela} and Jinghong Ma and Sandra Daack-Hirsch and Brion Maher and Raffensperger, {Lisa M.} and Russo, {Erilynn T.} and Vieira, {Alexandre R.} and Catherine Dod{\'e} and Moosa Mohammad and Marazita, {Mary L.} and Murray, {Jeffrey C.}",
year = "2007",
month = "3",
day = "13",
doi = "10.1073/pnas.0607956104",
language = "English (US)",
volume = "104",
pages = "4512--4517",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "11",

}

TY - JOUR

T1 - Impaired FGF signaling contributes to cleft lip and palate

AU - Riley, Bridget M.

AU - Mansilla, M. Adela

AU - Ma, Jinghong

AU - Daack-Hirsch, Sandra

AU - Maher, Brion

AU - Raffensperger, Lisa M.

AU - Russo, Erilynn T.

AU - Vieira, Alexandre R.

AU - Dodé, Catherine

AU - Mohammad, Moosa

AU - Marazita, Mary L.

AU - Murray, Jeffrey C.

PY - 2007/3/13

Y1 - 2007/3/13

N2 - 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.

AB - 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.

KW - Cleft palate

KW - Fibroblast growth factor

KW - Fibroblast growth factor receptor

KW - Single-nucleotide polymorphism

UR - http://www.scopus.com/inward/record.url?scp=34248347081&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34248347081&partnerID=8YFLogxK

U2 - 10.1073/pnas.0607956104

DO - 10.1073/pnas.0607956104

M3 - Article

VL - 104

SP - 4512

EP - 4517

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 11

ER -