Human Molecular Genetics Advance Access originally published online on September 23, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2003, Vol. 12, No. 22 2993-3005
DOI: 10.1093/hmg/ddg324
© 2003 Oxford University Press
Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1
1Department of Medical Genetics and 2Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 and 3Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-8002, USA
Received July 17, 2003; Revised September 3, 2003; Accepted September 15, 2003
Five missense mutations (P79L, P79T, I91S, I91T and R127H) within the forkhead DNA-binding domain of the FOXC1 transcription factor, identified in patients with Axenfeld–Rieger (AR) malformations, were studied to identify the effects of these mutations on FOXC1 structure and function. Molecular modeling and threading analyses predict that the I91S and T mutations may generate local disruptions to the structure of the forkhead domain while the R127H mutation alters the electrostatic charge of the DNA binding surface of the forkhead domain. The P79L and T mutations are not predicted to grossly perturb the structure of the forkhead domain. Biological analyses indicate that all of these missense mutations cause a range of FOXC1 perturbations, including nuclear localization defects, reduced or abolished DNA binding capacity, and a reduction in the transactivation capacity of FOXC1. These experiments extend our previous hypothesis that reduced transactivation of appropriate target genes by FOXC1, underlie AR malformations mapping to human chromosome 6p25. Importantly, these results can also be applied to predict the consequences of the molecular effects of mutations of other FOX genes that have analogous missense mutations, including FOXP2, FOXE3 and FOXC2.
* To whom correspondence should be addressed at: 832 Medical Sciences Building, University of Alberta, Edmonton, AB, Canada, T6G 2H7. Tel: +1 7804929805; Fax: +1 7804926934; Email: mwalter{at}ualberta.ca
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. M. Skarie and B. A. Link FoxC1 Is Essential for Vascular Basement Membrane Integrity and Hyaloid Vessel Morphogenesis Invest. Ophthalmol. Vis. Sci., November 1, 2009; 50(11): 5026 - 5034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Huang, J. Chi, F. B. Berry, T. K. Footz, M. W. Sharp, and M. A. Walter Human p32 Is a Novel FOXC1-Interacting Protein That Regulates FOXC1 Transcriptional Activity in Ocular Cells Invest. Ophthalmol. Vis. Sci., December 1, 2008; 49(12): 5243 - 5249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Beysen, L. Moumne, R. Veitia, H. Peters, B. P. Leroy, A. De Paepe, and E. De Baere Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation Hum. Mol. Genet., July 1, 2008; 17(13): 2030 - 2038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. B. Berry, J. M. Skarie, F. Mirzayans, Y. Fortin, T. J. Hudson, V. Raymond, B. A. Link, and M. A. Walter FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A Hum. Mol. Genet., February 14, 2008; 17(4): 490 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Strungaru, I. Dinu, and M. A. Walter Genotype-Phenotype Correlations in Axenfeld-Rieger Malformation and Glaucoma Patients with FOXC1 and PITX2 Mutations Invest. Ophthalmol. Vis. Sci., January 1, 2007; 48(1): 228 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. A. Ito, T. K. Footz, T. C. Murphy, W. Courtens, and M. A. Walter Analyses of a Novel L130F Missense Mutation in FOXC1 Arch Ophthalmol, January 1, 2007; 125(1): 128 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Vernes, J. Nicod, F. M. Elahi, J. A. Coventry, N. Kenny, A.-M. Coupe, L. E. Bird, K. E. Davies, and S. E. Fisher Functional genetic analysis of mutations implicated in a human speech and language disorder Hum. Mol. Genet., November 1, 2006; 15(21): 3154 - 3167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tamimi, J. M. Skarie, T. Footz, F. B. Berry, B. A. Link, and M. A. Walter FGF19 is a target for FOXC1 regulation in ciliary body-derived cells Hum. Mol. Genet., November 1, 2006; 15(21): 3229 - 3240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Burch, I. V. Yang, G. S. Whitehead, F. G. Chao, K. G. Berman, and D. A. Schwartz The transcriptional response to lipopolysaccharide reveals a role for interferon-{gamma} in lung neutrophil recruitment Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L677 - L682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-L. Tsai, C.-Y. Huang, C.-H. Chang, Y.-J. Sun, W.-J. Chuang, and C.-D. Hsiao Crystal Structure of the Human FOXK1a-DNA Complex and Its Implications on the Diverse Binding Specificity of Winged Helix/Forkhead Proteins J. Biol. Chem., June 23, 2006; 281(25): 17400 - 17409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. B. Berry, M. A. Lines, J. M. Oas, T. Footz, D. A. Underhill, P. J. Gage, and M. A. Walter Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis Hum. Mol. Genet., March 15, 2006; 15(6): 905 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. B. Berry, Y. Tamimi, M. V. Carle, O. J. Lehmann, and M. A. Walter The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis Hum. Mol. Genet., September 15, 2005; 14(18): 2619 - 2627. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. B. Berry, M. A. O'Neill, M. Coca-Prados, and M. A. Walter FOXC1 Transcriptional Regulatory Activity Is Impaired by PBX1 in a Filamin A-Mediated Manner Mol. Cell. Biol., February 15, 2005; 25(4): 1415 - 1424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Caburet, A Demarez, L Moumne, M Fellous, E De Baere, and R A Veitia A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation J. Med. Genet., December 1, 2004; 41(12): 932 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Saleem, S. Banerjee-Basu, T. C. Murphy, A. Baxevanis, and M. A. Walter Essential structural and functional determinants within the forkhead domain of FOXC1 Nucleic Acids Res., August 6, 2004; 32(14): 4182 - 4193. [Abstract] [Full Text] [PDF]
|
|