| First Author | Göppner C | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100074 | PubMed ID | 33187987 |
| Mgi Jnum | J:331730 | Mgi Id | MGI:6807301 |
| Doi | 10.1074/jbc.RA120.016031 | Citation | Goppner C, et al. (2021) Cellular basis of ClC-2 Cl(-) channel-related brain and testis pathologies. J Biol Chem 296:100074 |
| abstractText | 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 that 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. |
