A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia

Citations Over TimeTop 10% of 2005 papers

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.

Related Papers

• → Chediak–Higashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype(2013)28 cited
• → Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30(2010)25 cited
• → Characterization ofp53 mutants identified in human tumors with a missense mutation in the tetramerization domain(1998)27 cited
• → Acid alpha-glucosidase deficiency: Identification and expression of a missense mutation (S529V) in a Japanese adult phenotype(1996)14 cited
• → Acid alpha-glucosidase deficiency: identification and expression of a missense mutation (S529V) in a Japanese adult phenotype(1996)2 cited