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Cellular basis of ClC-2 Cl(-) channel-related brain and testis pathologies

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Item Type:Article
Title:Cellular basis of ClC-2 Cl(-) channel-related brain and testis pathologies
Creators Name:Göppner, C. and Soria, A.H. and Hoegg-Beiler, M.B. and Jentsch, T.J.
Abstract:The ClC-2 chloride channel is expressed in the plasma membrane of almost all mammalian cells. Mutations that cause the loss of ClC-2 function lead to retinal and testicular degeneration and leukodystrophy, whereas gain of function mutations cause hyper­aldosteronism. Leukodystrophy is also observed with a loss of GlialCAM, a cell adhesion molecule which binds to ClC-2 in glia. GlialCAM changes the localization of ClC-2 and opens the channel by altering its gating. We now used cell-type specific deletion of ClC-2 in mice to show that retinal and testicular degeneration depend on a loss of ClC-2 in retinal pigment epithelial cells and Sertoli cells, respectively, whereas leukodystrophy was fully developed only when ClC-2 was disrupted in both astrocytes and oligodendrocytes. The leukodystrophy of Glialcam(-/-) mice could not be rescued by crosses with Clcn2(op/op) mice in which a mutation mimics the ‘opening’ of ClC-2 by GlialCAM. These data indicate that GlialCAM-induced changes in biophysical properties of ClC-2 are irrelevant for GLIALCAM-related leukodystrophy. Taken together, our findings suggest that the pathology caused by Clcn2 disruption results from disturbed extracellular ion homeostasis and identifies the cells involved in this process.
Keywords:Anion Channel, Infertility, Leukoencephalopathy, Myelin Vacuolization, RPE, HepaCAM, Aldosteronism, Animals, Mice
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology
Volume:296
Page Range:100074
Date:4 January 2021
Official Publication:https://doi.org/10.1074/jbc.RA120.016031
PubMed:View item in PubMed

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