A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia

Development. 2005 Oct;132(19):4375-86. doi: 10.1242/dev.02011.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Animals
  • Biomechanical Phenomena
  • Bone Density
  • Bone and Bones / abnormalities
  • Bone and Bones / physiopathology
  • Connexin 43 / genetics*
  • Connexin 43 / metabolism
  • Craniofacial Abnormalities / genetics
  • Dental Enamel Hypoplasia / genetics
  • Disease Models, Animal*
  • Ethylnitrosourea
  • Eye Abnormalities / genetics
  • Gap Junctions / physiology
  • Gap Junctions / ultrastructure
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / physiopathology
  • Humans
  • Mice
  • Penetrance
  • Point Mutation*
  • Stem Cells / pathology
  • Syndactyly / genetics


  • Connexin 43
  • Ethylnitrosourea