Cellular basis of ClC-2 Cl− channel–related brain and testis pathologies

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 Clcn2op/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.

Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect

“…In humans, loss-of-function mutations in the CLCN2 gene are associated with a subtype of the white matter disorder leukodystrophy, also known as CLCN2 -related leukoencephalopathy, manifesting as intramyelinic edema in the brain and perhaps infertility [ 11 , 12 , 13 , 14 ]. Along with other studies in different types of Clcn2 -deficient mice [ 15 , 16 ], these findings support the notion that the ClC-2 channel is important for extracellular ion homeostasis in the brain and the testis.…”

Apical CLC‐2 in retinal pigment epithelium is crucial for survival of the outer retina

“…This does not seem the case, as RPE‐specific transduction of CLC‐2 into RPE cells rescues retinal degeneration both structurally (Figure 6) and functionally (Figure 7). Furthermore, RPE‐specific knockout of CLC‐2 is sufficient to cause retinal degeneration, as recently demonstrated by a recent publication by Jentsch and coworkers that came out while this manuscript was in preparation 40 . Our surprising finding that CLC‐2 is expressed apically in RPE cells provides a possible explanation for these findings.…”

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

“…Several findings suggest that CLCN2 downregulation in MS may reflect altered WM integrity and/or contribute to the mechanisms of myelin destruction: first, ClCN2 −/− mice exhibit abnormal WM morphology (Blanz et al, 2007 ); second, loss-of-function CLCN2 mutations lead to leukodystrophy; third, loss of cell adhesion molecule GlialCAM, which binds to ClC-2 in glia, is associated with leukodystrophy (Jeworutzki et al, 2012 ; Hoegg-Beiler et al, 2014 ). Of note, though, is a recent report showing that leukodystrophy fully develops only when ClC-2 is disrupted in both astrocytes and oligodendrocytes (Goppner et al, 2020 ). It remains to be investigated whether CLC-2 loss in glia contributes to the failure of myelin repair in human CA lesions.…”