Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction
2010 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction
Diekmann, S.; Henneke, M.; Burckhardt, B. C. & Gärtner, J. (2010)
European Journal of Human Genetics, 18(9) pp. 985-992. DOI: https://doi.org/10.1038/ejhg.2010.61
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- Authors
- Diekmann, Simone; Henneke, Marco; Burckhardt, Birgitta C. ; Gärtner, Jutta
- Abstract
- Autosomal recessive mutations in the GJA12/GJC2 gene encoding the gap junction protein connexin47 (C x 47) cause a form of Pelizaeus-Merzbacher-like disease (PMLD) with hypomyelination, nystagmus, impaired psychomotor development and progressive spasticity. We investigated the functional consequences of four C x 47 missense mutations (G149S, G236R, T265A, and T398I) and one C x 47 complex mutation (A98G_V99insT) by immunoblot analysis and immunocytochemistry in transfected communication-incompetent HeLa cells and in OLI-neu cells. All studied C x 47 mutants, except G236R, generated stable proteins in transfected HeLa cells and OLI-neu cells. The mutants T265A and A98G_V99insT were retained in the ER, T398I formed gap junctional plaques at the plasma membrane, and G149S showed both, structures at the plasma membrane and ER localization. Two-microelectrode voltage clamp analyses in Xenopus laevis oocytes injected with wild-type and mutant C x 47 cRNA revealed reduced hemichannel currents for G236R, T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wild-type. For C x 47 mutant T398I, our results indicate a defect in hemichannel function, whereas C x 47 mutants G149S, G236R, T265A, and A98G_V99insT are predicted to result in a loss of C x 47 hemichannel function. Thus, PMLD is likely to be caused by two different disease mechanisms: a loss of function and a dysfunction. European Journal of Human Genetics (2010) 18, 985-992; doi:10.1038/ejhg.2010.61; published online 5 May 2010
- Issue Date
- 2010
- Publisher
- Nature Publishing Group
- Journal
- European Journal of Human Genetics
- ISSN
- 1018-4813