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Impaired FGF signaling contributes to cleft lip and palate

Bridget M Riley1, M Adela Mansilla, Jinghong Ma

  • 1Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 16, 2007
PubMed

Insights

Genetic disruptions in the FGF signaling pathway are linked to nonsyndromic cleft lip and palate (NS CLP). This study identified mutations and genetic associations, suggesting the pathway contributes to 3-5% of NS CLP cases.

Area of Science:

  • Genetics
  • Developmental Biology
  • Craniofacial Development

Background:

  • Nonsyndromic cleft lip and palate (NS CLP) is a complex birth defect with genetic and environmental origins.
  • Fibroblast Growth Factor (FGF) and FGF Receptor (FGFR) genes are crucial for craniofacial development and mutations can cause clefting syndromes.

Purpose of the Study:

  • To investigate the role of the FGF signaling pathway in the etiology of NS CLP.
  • To identify genetic variants and associations within key FGF and FGFR genes in NS CLP patients.

Main Methods:

  • Sequencing of coding regions for 12 genes (FGFR1-3, FGF2-4, FGF7-10, FGF18, NUDT6).
  • Protein structure analysis to predict the functional impact of identified amino acid variants.
  • Single Nucleotide Polymorphism (SNP) genotyping and association testing for NS CLP.

Main Results:

  • Seven likely disease-causing mutations were identified, including nonsense and de novo missense mutations in FGFR1 and FGF8.
  • Structural analysis indicated impaired protein function for variants in FGFR1, FGFR2, and FGF8.
  • Association testing revealed significant links between NS CLP and SNPs in FGF3, FGF7, FGF10, FGF18, and FGFR1.

Conclusions:

  • The FGF signaling pathway is implicated in a subset (3-5%) of NS CLP cases.
  • Identified mutations and associations provide insights into the genetic basis of NS CLP.
  • Findings suggest the FGF pathway should be considered in the clinical management of cleft lip and palate.

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