Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1

Am J Hum Genet. 2001 Mar;68(3):627-41. doi: 10.1086/318792.


Five missense mutations of the winged-helix FOXC1 transcription factor, found in patients with Axenfeld-Rieger (AR) malformations, were investigated for their effects on FOXC1 structure and function. Molecular modeling of the FOXC1 forkhead domain predicted that the missense mutations did not alter FOXC1 structure. Biochemical analyses indicated that, whereas all mutant proteins correctly localize to the cell nucleus, the I87M mutation reduced FOXC1-protein levels. DNA-binding experiments revealed that, although the S82T and S131L mutations decreased DNA binding, the F112S and I126M mutations did not. However, the F112S and I126M mutations decrease the transactivation ability of FOXC1. All the FOXC1 mutations had the net effect of reducing FOXC1 transactivation ability. These results indicate that the FOXC1 forkhead domain contains separable DNA-binding and transactivation functions. In addition, these findings demonstrate that reduced stability, DNA binding, or transactivation, all causing a decrease in the ability of FOXC1 to transactivate genes, can underlie AR malformations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins*
  • Eye Abnormalities / genetics*
  • Forkhead Transcription Factors
  • Humans
  • Iris / abnormalities*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Protein Conformation
  • Protein Structure, Secondary
  • Rats
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation


  • DNA-Binding Proteins
  • FOXC1 protein, human
  • Forkhead Transcription Factors
  • Foxc1 protein, mouse
  • Transcription Factors

Associated data

  • GENBANK/AF048693
  • GENBANK/AF076292
  • GENBANK/AF110506
  • GENBANK/AF153341
  • GENBANK/U13219
  • GENBANK/U13220
  • GENBANK/U13222
  • GENBANK/Y08223
  • RefSeq/NM_008592
  • RefSeq/NM_012183