Skip Navigation



Human Molecular Genetics Advance Access published online on August 4, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi295
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/18/2619    most recent
ddi295v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Berry, F. B.
Right arrow Articles by Walter, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Berry, F. B.
Right arrow Articles by Walter, M. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 8, 2005
Revised July 28, 2005
Accepted July 28, 2005

Article

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

Fred B. Berry 1*, Yahya Tamimi 2, Michelle V. Carle 3, Ordan J. Lehmann 4, and Michael A. Walter 4

1 Departments of Ophthalmology, 832 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
2 Medical Genetics, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
3 Departments of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
4 Departments of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7; Medical Genetics, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

* To whom correspondence should be addressed.
Fred B. Berry, E-mail: fberry{at}ualberta.ca


  Abstract

The FOX family of transcription factor genes is an evolutionary conserved, yet functionally diverse class of transcription factors that are important for regulation of energy homeostasis, development and oncogenesis. The proteins encoded by FOX genes are characterized by a conserved DNA-binding domain known as the Forkhead domain. To date disease-causing mutations have been identified in eight human FOX genes. Many of these mutations result in single amino acid substitutions in the Forkhead domain. We analyzed the molecular consequences of two disease-causing missense mutations (R121H and S125L) occurring in the Forkhead domain of the FOXC2 gene that were identified in patients with hereditary lymphedema with distichiasis to test the predictive capacity of a forkhead domain structure/function model. Based on the FOXC2 solution structure, both FOXC2 missense mutations are located on the DNA-recognition helix of the forkhead domain. A mutation model based on the parologous FOXC1 protein predicts that these FOXC2 missense mutations will impair the DNA-binding and transcriptional activation ability of the FOXC2 protein. When these mutations were analyzed biochemically, we found that both mutations did indeed reduce the DNA-binding and transcriptional capacity. In addition the R121H mutation affected nuclear localization of FOXC2. Together these data indicate that these FOXC2 missense mutations are functional nulls, that FOXC2 haploinsufficiency underlies hereditary lymphedema with distichiasis, and validates the predictive ability of the FOXC1-based Forkhead domain mutational model.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
A. Dipietromaria, B. A. Benayoun, A.-L. Todeschini, I. Rivals, C. Bazin, and R. A. Veitia
Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems
Hum. Mol. Genet., September 1, 2009; 18(17): 3324 - 3333.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
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]

Home page
 Hum Mol GenetHome page
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]

Home page
 CirculationHome page
R. H. Mellor, G. Brice, A. W.B. Stanton, J. French, A. Smith, S. Jeffery, J. R. Levick, K. G. Burnand, and P. S. Mortimer
Mutations in FOXC2 Are Strongly Associated With Primary Valve Failure in Veins of the Lower Limb
Circulation, April 10, 2007; 115(14): 1912 - 1920.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
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]

Home page
 Hum Mol GenetHome page
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]

Home page
 Hum Mol GenetHome page
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]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.