A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia |
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Authors: | Flenniken Ann M Osborne Lucy R Anderson Nicole Ciliberti Nadia Fleming Craig Gittens Joanne E I Gong Xiang-Qun Kelsey Lois B Lounsbury Crystal Moreno Luisa Nieman Brian J Peterson Katie Qu Dawei Roscoe Wendi Shao Qing Tong Dan Veitch Gregory I L Voronina Irina Vukobradovic Igor Wood Geoffrey A Zhu Yonghong Zirngibl Ralph A Aubin Jane E Bai Donglin Bruneau Benoit G Grynpas Marc Henderson Janet E Henkelman R Mark McKerlie Colin Sled John G Stanford William L Laird Dale W Kidder Gerald M Adamson S Lee Rossant Janet |
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Institution: | Centre For Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. |
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Abstract: | 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. |
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