The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans

Hum Mol Genet. 2008 Feb 15;17(4):539-54. doi: 10.1093/hmg/ddm329. Epub 2007 Nov 13.


Oculodentodigital dysplasia (ODDD) is a dominant negatively inherited disorder with variable but characteristic anomalies of the fingers and toes, eyes, face and teeth, which are caused by mutations in the connexin 43 (Cx43) gene. All mutations analyzed so far have a negative influence on the conductance through gap junctional channels and hemichannels, as well as trafficking of Cx43 protein in transfected cells. In this study, we inserted the human Cx43G138R point mutation into the mouse Cx43 gene and generated mice conditionally expressing this mutation. All ODDD phenotypic manifestations observed in humans, including syndactyly and enamel hypoplasia as well as craniofacial, bone and heart anomalies, were also observed with significant penetrance in Cx43G138R mice. When this mutation was specifically expressed in cardiomyocytes, characteristic alterations in the electrocardiogram and spontaneous arrhythmias were recorded. In vitro studies with Cx43G138R-expressing cells revealed loss of the Cx43 P2 phosphorylation state, which was also absent in the mutated hearts. This loss has previously been associated with gap junctional dysfunction and increased cellular ATP release. The Cx43G138R mutated mice show significantly increased arrhythmogeneity ex vivo in Langendorff experiments with explanted hearts and in vivo in particular under hypoxic conditions. Our results suggest that the increased activity of ATP-releasing channels in Cx43G138R mutated cardiomyocytes may further reduce the already decreased gap junctional communication and thus aggravate arrhythmogenesis in the mouse mutant.

Publication types

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

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / metabolism
  • Base Sequence
  • Connexin 43 / chemistry
  • Connexin 43 / genetics*
  • Connexin 43 / metabolism
  • Craniofacial Abnormalities / genetics
  • DNA Primers / genetics
  • Disease Models, Animal
  • Eye Abnormalities / genetics*
  • Fingers / abnormalities
  • Gap Junctions / metabolism
  • HeLa Cells
  • Heterozygote
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Myocytes, Cardiac / metabolism
  • Phenotype
  • Point Mutation*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Syndactyly / genetics
  • Syndrome
  • Toes / abnormalities
  • Tooth Abnormalities / genetics*


  • Connexin 43
  • DNA Primers
  • GJA1 protein, human
  • Recombinant Fusion Proteins
  • Adenosine Triphosphate