Human Molecular Genetics, 2003, Vol. 12, No. 12 1439-1447
DOI: 10.1093/hmg/ddg158
© 2003 Oxford University Press
Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia
1Institut für Biochemie, Universität Erlangen, D-91054 Erlangen, Germany, 2Children's Hospital and Regional Medical Center, Seattle, WA 98105-0371, USA, 3Center for Medical Genetics, University Hospital VUB, B-1090 Brussels, Belgium and 4Institute of Human Genetics and Anthropology, University of Freiburg, D-79106 Freiburg, Germany
Received December 5, 2002; Accepted April 23, 2003
Campomelic dysplasia (CD) is a semilethal osteochondrodysplasia, characterized by skeletal anomalies that include bending of the long bones, and by XY sex reversal. CD results from haploinsufficiency for the transcription factor SOX9, a key regulator at various steps of cartilage differentiation and of early testis development. Two functional domains are so far recognized for SOX9, a high-mobility group (HMG) DNA-binding domain and a C-terminal transactivation domain. We present two CD patients with de novo mutations in a conserved region preceding the HMG domain. A long-term survivor with the acampomelic form of CD has an A76E amino acid substitution, while a severely affected CD patient had an in-frame deletion of amino acid residues 66–75. The conserved domain has been shown to function in the related transcription factor SOX10 as a DNA-dependent dimerization domain. We show that, like SOX10, SOX9 also binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes Col11a2 and CD-Rap. Dimerization and the resulting capacity to activate promoters via dimeric binding sites is lost in both mutant SOX9 proteins while other features involved in SOX9 function remained unaltered. These findings establish the dimerization domain as the third domain essential for SOX9 function during chondrogenesis.
* To whom correspondence should be addressed at: Institute of Human Genetics and Anthropology, Breisacherstr. 33, D-79106 Freiburg, Germany. Tel: +49 7612707030; Fax: +49 7612707041; Email: scherer{at}ukl.uni-freiburg.de
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Hattori, F. Coustry, S. Stephens, H. Eberspaecher, M. Takigawa, H. Yasuda, and B. de Crombrugghe Transcriptional regulation of chondrogenesis by coactivator Tip60 via chromatin association with Sox9 and Sox5 Nucleic Acids Res., May 1, 2008; 36(9): 3011 - 3024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Davies, L.-W. Chang, D. Patra, X. Xing, K. Posey, J. Hecht, G. D. Stormo, and L. J. Sandell Computational identification and functional validation of regulatory motifs in cartilage-expressed genes Genome Res., October 1, 2007; 17(10): 1438 - 1447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Guimont, F. Grondin, and C. M. Dubois Sox9-dependent transcriptional regulation of the proprotein convertase furin Am J Physiol Cell Physiol, July 1, 2007; 293(1): C172 - C183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Wilhelm, R. Hiramatsu, H. Mizusaki, L. Widjaja, A. N. Combes, Y. Kanai, and P. Koopman SOX9 Regulates Prostaglandin D Synthase Gene Transcription in Vivo to Ensure Testis Development J. Biol. Chem., April 6, 2007; 282(14): 10553 - 10560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Genzer and L. C. Bridgewater A Col9a1 enhancer element activated by two interdependent SOX9 dimers Nucleic Acids Res., February 28, 2007; 35(4): 1178 - 1186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. H. Evans and R. N. Rosier Molecular Biology in Orthopaedics: The Advent of Molecular Orthopaedics J. Bone Joint Surg. Am., November 1, 2005; 87(11): 2550 - 2564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Imamura, C. Imamura, Y. Iwamoto, and L. J. Sandell Transcriptional Co-activators CREB-binding Protein/p300 Increase Chondrocyte Cd-rap Gene Expression by Multiple Mechanisms Including Sequestration of the Repressor CCAAT/Enhancer-binding Protein J. Biol. Chem., April 29, 2005; 280(17): 16625 - 16634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-L. Yan, J. Willoughby, D. Liu, J. G. Crump, C. Wilson, C. T. Miller, A. Singer, C. Kimmel, M. Westerfield, and J. H. Postlethwait A pair of Sox: distinct and overlapping functions of zebrafish sox9 co-orthologs in craniofacial and pectoral fin development Development, March 1, 2005; 132(5): 1069 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chikuda, F. Kugimiya, K. Hoshi, T. Ikeda, T. Ogasawara, T. Shimoaka, H. Kawano, S. Kamekura, A. Tsuchida, N. Yokoi, et al. Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes Genes & Dev., October 1, 2004; 18(19): 2418 - 2429. [Abstract] [Full Text] [PDF]
|
|