NDLI: Pelizaeus–Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction

Content Provider	PubMed Central
Author	Diekmann, Simone Henneke, Marco Burckhardt, Birgitta C. Gärtner, Jutta
Copyright Year	2010
Abstract	Autosomal recessive mutations in the GJA12/GJC2 gene encoding the gap junction protein connexin47 (C × 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 × 47 missense mutations (G149S, G236R, T265A, and T398I) and one C × 47 complex mutation (A98G_V99insT) by immunoblot analysis and immunocytochemistry in transfected communication-incompetent HeLa cells and in OLI-neu cells. All studied C × 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 × 47 cRNA revealed reduced hemichannel currents for G236R, T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wild-type. For C × 47 mutant T398I, our results indicate a defect in hemichannel function, whereas C × 47 mutants G149S, G236R, T265A, and A98G_V99insT are predicted to result in a loss of C × 47 hemichannel function. Thus, PMLD is likely to be caused by two different disease mechanisms: a loss of function and a dysfunction.
Related Links	http://dx.doi.org/10.1038/ejhg.2010.61
Ending Page	992
Page Count	8
Starting Page	985
File Format	PDF
ISSN	10184813
e-ISSN	14765438
Journal	European Journal of Human Genetics
Issue Number	9
Volume Number	18
Language	English
Publisher	Nature Publishing Group
Publisher Date	2010-09-01
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Genetics(clinical) Genetics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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