Journal of Membrane Biology

, Volume 219, Issue 1, pp 9–17

Some Oculodentodigital Dysplasia-Associated Cx43 Mutations Cause Increased Hemichannel Activity in Addition to Deficient Gap Junction Channels

  • Radoslaw Dobrowolski
  • Annette Sommershof
  • Klaus Willecke
Article

DOI: 10.1007/s00232-007-9055-7

Cite this article as:
Dobrowolski, R., Sommershof, A. & Willecke, K. J Membrane Biol (2007) 219: 9. doi:10.1007/s00232-007-9055-7

Abstract

Oculodentodigital dysplasia (ODDD) is a dominantly inherited human disorder associated with different symptoms like craniofacial anomalies, syndactyly and heart dysfunction. ODDD is caused by mutations in the GJA1 gene encoding the gap junction protein connexin43 (Cx43). Here, we have characterized four Cx43 mutations (I31M, G138R, G143S and H194P) after stable expression in HeLa cells. In patients, the I31M and G138R mutations showed all phenotypic characteristics of ODDD, whereas G143S did not result in facial abnormalities and H194P mutated patients exhibited no syndactylies. In transfected HeLa cells, these mutations led to lack of the P2 phosphorylation state of the Cx43 protein, complete inhibition of gap junctional coupling measured by neurobiotin transfer and increased hemichannel activity. In addition, altered trafficking and delayed degradation were found in these mutants by immunofluorescence and pulse-chase analyses. In G138R and G143S mutants, the increased hemichannel activity correlated with an increased half-time of the Cx43 protein. However, the I31M mutated protein showed no extended half-time. Thus, the increased hemichannel activity may be directly caused by an altered conformation of the mutated channel forming protein. We hypothesize that increased hemichannel activity may aggravate the phenotypic abnormalities in ODDD patients who are deficient in Cx43 gap junction channels.

Keywords

Gap junctionConnexinCx43HemichannelOculodentodigital dysplasia

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Radoslaw Dobrowolski
    • 1
  • Annette Sommershof
    • 1
    • 2
  • Klaus Willecke
    • 1
  1. 1.Institute of GeneticsUniversity of BonnBonnGermany
  2. 2.Department of Biology/ImmunologyUniversity of KonstanzKonstanzGermany