|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online September 9, 2005
doi: 10.1242/10.1242/dev.02011
1 Centre For Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount
Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
2 Department of Medicine, Medical Sciences Building, 1 King's College Circle,
University of Toronto, Toronto, Ontario M5S 1A8, Canada
3 Department of Molecular and Medical Genetics, Medical Sciences Building, 1
King's College Circle, University of Toronto, Toronto, Ontario M5S 1A8,
Canada
4 Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8,
Canada
5 Institute of Biomaterials and Biomedical Engineering, University of Toronto,
Toronto, Ontario M5G 1X8, Canada
6 Department of Physiology and Pharmacology, University of Western Ontario,
Dental Science Building, London, Ontario N6A 5C1, Canada
7 Department of Anatomy and Cell Biology, University of Western Ontario, Dental
Science Building, London, Ontario N6A 5C1, Canada
8 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario
M5G 1X8, Canada
9 Mouse Imaging Centre, The Hospital for Sick Children, 555 University Avenue
Toronto, Ontario M5G 1X8, Canada
10 Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S
1A8, Canada
11 Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario M5S
1A8, Canada
12 Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto,
Toronto, Ontario M5S 1A8, Canada
13 Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto, Ontario M5S 1A8, Canada
14 Department of Medicine and Centre for Bone and Periodontal Research, McGill
University, 740 Avenue Dr Penfield, Montreal, Quebec H3A 1A4, Canada
15 Integrative Biology Research Program, The Hospital for Sick Children, Toronto,
Ontario M5S 1A8, Canada
16 Department of Obstetrics and Gynecology, University of Toronto, Toronto,
Ontario M5S 1A8, Canada
Author for correspondence (e-mail:
rossant{at}mshri.on.ca)
Accepted 26 July 2005
Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder characterized by pleiotropic developmental anomalies of the limbs, teeth, face and eyes that was shown recently to be caused by mutations in the gap junction protein alpha 1 gene (GJA1), encoding connexin 43 (Cx43). In the course of performing an N-ethyl-N-nitrosourea mutagenesis screen, we identified a dominant mouse mutation that exhibits many classic symptoms of ODDD, including syndactyly, enamel hypoplasia, craniofacial anomalies and cardiac dysfunction. Positional cloning revealed that these mice carry a point mutation in Gja1 leading to the substitution of a highly conserved amino acid (G60S) in Cx43. In vivo and in vitro studies revealed that the mutant Cx43 protein acts in a dominant-negative fashion to disrupt gap junction assembly and function. In addition to the classic features of ODDD, these mutant mice also showed decreased bone mass and mechanical strength, as well as altered hematopoietic stem cell and progenitor populations. Thus, these mice represent an experimental model with which to explore the clinical manifestations of ODDD and to evaluate potential intervention strategies.
Key words: Oculodentodigital dysplasia, Connexin 43, Missense mutation, Mouse model
Related articles in Development:
This article has been cited by other articles:
|
|
 |
|
  J. L. Manias, I. Plante, X.-Q. Gong, Q. Shao, J. Churko, D. Bai, and D. W. Laird Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant Cardiovasc Res, December 1, 2008; 80(3): 385 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fenwick, R.J. Richardson, J. Butterworth, M.J. Barron, and M.J. Dixon Novel Mutations in GJA1 Cause Oculodentodigital syndrome J. Dent. Res., November 1, 2008; 87(11): 1021 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Lisewski, Y. Shi, U. Wrackmeyer, R. Fischer, C. Chen, A. Schirdewan, R. Juttner, F. Rathjen, W. Poller, M. H. Radke, et al. The tight junction protein CAR regulates cardiac conduction and cell-cell communication J. Exp. Med., September 29, 2008; 205(10): 2369 - 2379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Langlois, K. N. Cowan, Q. Shao, B. J. Cowan, and D. W. Laird Caveolin-1 and -2 Interact with Connexin43 and Regulate Gap Junctional Intercellular Communication in Keratinocytes Mol. Biol. Cell, March 1, 2008; 19(3): 912 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Dobrowolski, P. Sasse, J. W. Schrickel, M. Watkins, J.-S. Kim, M. Rackauskas, C. Troatz, A. Ghanem, K. Tiemann, J. Degen, et al. The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans Hum. Mol. Genet., February 14, 2008; 17(4): 539 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Laird Closing the Gap on Autosomal Dominant Connexin-26 and Connexin-43 Mutants Linked to Human Disease J. Biol. Chem., February 8, 2008; 283(6): 2997 - 3001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kalcheva, J. Qu, N. Sandeep, L. Garcia, J. Zhang, Z. Wang, P. D. Lampe, S. O. Suadicani, D. C. Spray, and G. I. Fishman Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia PNAS, December 18, 2007; 104(51): 20512 - 20516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Y. Li, D. Colley, K. J. Barr, S.-P. Yee, and G. M. Kidder Rescue of oogenesis in Cx37-null mutant mice by oocyte-specific replacement with Cx43 J. Cell Sci., December 1, 2007; 120(23): 4117 - 4125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Langlois, A. C. Maher, J. L. Manias, Q. Shao, G. M. Kidder, and D. W. Laird Connexin Levels Regulate Keratinocyte Differentiation in the Epidermis J. Biol. Chem., October 12, 2007; 282(41): 30171 - 30180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Q. Gong, Q. Shao, S. Langlois, D. Bai, and D. W. Laird Differential Potency of Dominant Negative Connexin43 Mutants in Oculodentodigital Dysplasia J. Biol. Chem., June 29, 2007; 282(26): 19190 - 19202. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Anderson, R. Zirngibi, F. Chen, C. Owen, L. Zitano, E. Lau, J. Aubin, and W. Stanford The Role of Gja1 Gap Junctions in the Bone Marrow Niche. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 1392 - 1392. [Abstract] [PDF]
|
|
|
|
|
|
M. R. Calera, H. L. Topley, Y. Liao, B. R. Duling, D. L. Paul, and D. A. Goodenough Connexin43 is required for production of the aqueous humor in the murine eye J. Cell Sci., November 1, 2006; 119(21): 4510 - 4519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Q. Gong, Q. Shao, C. S. Lounsbury, D. Bai, and D. W. Laird Functional Characterization of a GJA1 Frameshift Mutation Causing Oculodentodigital Dysplasia and Palmoplantar Keratoderma J. Biol. Chem., October 20, 2006; 281(42): 31801 - 31811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Chung, C. H. M. Castro, M. Watkins, J. P. Stains, M. Y. Chung, V. L. Szejnfeld, K. Willecke, M. Theis, and R. Civitelli Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43 J. Cell Sci., October 15, 2006; 119(20): 4187 - 4198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R J Richardson, S Joss, S Tomkin, M Ahmed, E Sheridan, and M J Dixon A nonsense mutation in the first transmembrane domain of connexin 43 underlies autosomal recessive oculodentodigital syndrome. J. Med. Genet., July 1, 2006; 43(7): e37 - e37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-h. Xia, H. Liu, D. Cheung, C. Cheng, E. Wang, X. Du, B. Beutler, W.-K. Lo, and X. Gong Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development and cataractogenesis Development, May 15, 2006; 133(10): 2033 - 2040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, V. V. Patel, and G. L. Radice Dysregulation of cell adhesion proteins and cardiac arrhythmogenesis. Clin. Med. Res., March 1, 2006; 4(1): 42 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Nieman, A. M. Flenniken, S. L. Adamson, R. M. Henkelman, and J. G. Sled Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography Physiol Genomics, January 12, 2006; 24(2): 154 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Tong, J. E. I. Gittens, G. M. Kidder, and D. Bai Patch-clamp study reveals that the importance of connexin43-mediated gap junctional communication for ovarian folliculogenesis is strain specific in the mouse Am J Physiol Cell Physiol, January 1, 2006; 290(1): C290 - C297. [Abstract] [Full Text] [PDF]
|
|
