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Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1

Ramsey A Saleem1, Sharmila Banerjee-Basu, Fred B Berry

  • 1Department of Human Genetics, University of Alberta, Edmonton, Canada, T6G 2H7.

Human Molecular Genetics
|September 25, 2003
PubMed

Insights

Five mutations in the FOXC1 gene disrupt its structure and function, leading to Axenfeld-Rieger malformations. These findings clarify the molecular basis of AR malformations and inform studies on related FOX genes.

Area of Science:

  • Genetics and Molecular Biology
  • Developmental Biology

Background:

  • Axenfeld-Rieger (AR) malformations are associated with mutations in the FOXC1 transcription factor.
  • The forkhead DNA-binding domain of FOXC1 is crucial for its function.

Purpose of the Study:

  • To investigate the structural and functional effects of five specific missense mutations (P79L, P79T, I91S, I91T, R127H) in the FOXC1 gene.
  • To understand how these mutations contribute to AR malformations.

Main Methods:

  • Molecular modeling and threading analyses to predict structural changes.
  • Biological assays to assess nuclear localization, DNA binding, and transactivation capacity.

Main Results:

  • Mutations I91S and I91T predicted to disrupt forkhead domain structure; R127H alters DNA binding surface charge.
  • P79L and P79T mutations are not predicted to cause major structural perturbations.
  • All five mutations resulted in impaired FOXC1 function, including nuclear import defects, reduced DNA binding, and decreased transactivation.

Conclusions:

  • Reduced transactivation of target genes by mutated FOXC1 underlies AR malformations.
  • These findings support the hypothesis linking FOXC1 dysfunction to AR malformations at chromosome 6p25.
  • The study's insights can predict the effects of similar mutations in other FOX genes (e.g., FOXP2, FOXE3, FOXC2).

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