Pelizaeus-Merzbacher like disease is caused not only by a loss of Connexin47 function but also by a hemichannel dysfunction - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue European Journal of Human Genetics Année : 2010

Pelizaeus-Merzbacher like disease is caused not only by a loss of Connexin47 function but also by a hemichannel dysfunction

Résumé

Autosomal recessive mutations in the GJA12/GJC2 gene encoding the gap junction protein connexin47 (Cx47) 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 Cx47 missense mutations (G149S, G236R, T265A, T398I) and one Cx47 complex mutation (A98G_V99insT) by immunoblot analysis and immunocytochemistry in transfected communication incompetent HeLa cells and in OLI-neu cells. All studied Cx47 mutants except G236R generated stable proteins in transfected HeLa cells and OLI-neu cells. 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 Cx47 cRNA revealed reduced hemichannel currents for G236R, T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wild-type. For Cx47 mutant T398I our results indicate a defect in hemichannel function, whereas Cx47 mutants G149S, G236R, T265A, and A98G_V99insT are predicted to result in a loss of Cx47 hemichannel function. Thus, PMLD is likely to be caused by two different disease mechanisms, a loss-of-function and a dysfunction.
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Dates et versions

hal-00533036 , version 1 (05-11-2010)

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Jutta Gärtner, Simone Diekmann, Marco Henneke, Birgitta C. Burckhardt. Pelizaeus-Merzbacher like disease is caused not only by a loss of Connexin47 function but also by a hemichannel dysfunction. European Journal of Human Genetics, 2010, ⟨10.1038/ejhg.2010.61⟩. ⟨hal-00533036⟩

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