Structural determinants of interaction, trafficking and function in the ClC‐2/MLC1 subunit GlialCAM involved in leukodystrophy

Capdevila-Nortes, Xavier; Jeworutzki, Elena; Elorza‐Vidal, Xabier; Barrallo-Gimeno, Alejandro; Pusch, Michael; Estévez, Raúl

doi:10.1113/jp270467

Cited by 18 publications

(23 citation statements)

References 39 publications

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“…It had been found that it is the extracellular domain of hepaCAM that is necessary for its targeting to cell junctions, and for its interactions with itself and with MLC1 and ClC-227. This finding is in line with our data that the mutations as well as the monoclonal antibody that interrupt the association of hepaCAM with connexin 43 are located in or target the extracellular domain.…”

Section: Discussionsupporting

confidence: 92%

HepaCAM associates with connexin 43 and enhances its localization in cellular junctions

Moh

Schwarz

2016

Sci Rep

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HepaCAM (GlialCAM) is frequently deleted in carcinomas, and reintroduction of hepaCAM into transformed cell lines reduces cellular growth and induces senescence. Mutations in HEPACAM give rise to the neurodegenerative disease megalencephalic leukoencephalopathy with subcortical cysts (MLC) since mutated hepaCAM prevents shuttling of MLC1 protein to astrocytic junctions in the plasma membrane. Here we identify that hepaCAM associates with connexin 43, a main component of gap junctions, and enhances connexin 43 localization to the plasma membrane at cellular junctions. HepaCAM also increases the levels of connexin 43, not by enhancing its transcription but by stabilizing connexin 43 protein. In the absence of hepaCAM, connexin 43 undergoes a faster degradation via the lysosomal pathway while proteasomal degradation seems not to be involved. Mutations in hepaCAM that cause MLC, or neutralization of hepaCAM by antibodies disrupt its association with connexin 43 at cellular junctions. By discovering the requirement of hepaCAM for localizing connexin 43, a well-established tumor suppressor, to cellular junctions and stabilizing it there, this study suggests a mechanism by which deletion of hepaCAM may support tumor progression.

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Section: Discussionsupporting

confidence: 92%

HepaCAM associates with connexin 43 and enhances its localization in cellular junctions

Moh

Schwarz

2016

Sci Rep

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“…A reduction in the ClC-2-mediated currents was observed in oligodendrocytes of Clcn2 KO mice and in A500V-ClC-2 expressing mammalian cells [8, 10], supporting the ideas of Depienne et al, who suggested that ClC-2 disruption might result in the disturbance of the compensation of action-potential-induced ion shifts [1], leading to osmotic intramyelinic edema [3]. Recent studies have shown that GlialCAM/MLC1 complex, which physically binds ClC-2 [11, 12], increased the activity of A500V-ClC-2 [8], while the additional disruption of GlialCAM aggravated the vacuolization in Clcn2 KO mice [10]. Together, these findings indicate that functions of the mutant ClC-2 protein are at least partly regulated by the GlialCAM/MLC1 by unknown molecular mechanisms possibly involved in the pathophysiology of CC2L.…”

Section: Resultsmentioning

confidence: 57%

CLCN2-related leukoencephalopathy: a case report and review of the literature

et al. 2019

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Background Loss-of-function mutations in the CLCN2 gene were recently discovered to be a cause of a type of leukodystrophy named CLCN2 -related leukoencephalopathy (CC2L), which is characterized by intramyelinic edema. Herein, we report a novel mutation in CLCN2 in an individual with leukodystrophy. Case presentation A 38-year-old woman presented with mild hand tremor, scanning speech, nystagmus, cerebellar ataxia in the upper limbs, memory decline, tinnitus, and dizziness. An ophthalmologic examination indicated macular atrophy, pigment epithelium atrophy and choroidal capillary atrophy. Brain magnetic resonance imaging (MRI) showed the diffuse white matter involvement of specific white matter tracts. Decreased diffusion anisotropy was detected in various brain regions of the patient. Diffusion tensor tractography (DTT) showed obviously thinner tracts of interest than in the controls, with a decreased fiber number (FN), increased radial diffusivity (RD) and unchanged axial diffusivity (AD). A novel homozygous c.2257C > T (p.Arg753Ter) mutation in exon 20 of the CLCN2 gene was identified. Conclusion CC2L is a rare condition characterized by diffuse edema involving specific fiber tracts that pass through the brainstem. The distinct MRI patterns could be a strong indication for CLCN2 gene analysis. The findings of our study may facilitate the understanding of the pathophysiology and clinical symptoms of this disease. Electronic supplementary material The online version of this article (10.1186/s12883-019-1390-7) contains supplementary material, which is available to authorized users.

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“…GlialCAM interacts with ClC-2 through its extracellular amino terminus and the first part of its single transmembrane span rather than through its cytosolic C terminus ( 12 , 42 ). Accordingly, GlialCAM directs ΔN-ClC-2, a mutant carrying a deletion in the cytosolic N terminus similar to that of ClC-2 op , to cell–cell contacts just like WT ClC-2 ( 12 ).…”

Section: Resultsmentioning

confidence: 99%

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

Göppner

Soria

Hoegg-Beiler

et al. 2021

Journal of Biological Chemistry

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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.

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Structural determinants of interaction, trafficking and function in the ClC‐2/MLC1 subunit GlialCAM involved in leukodystrophy

Cited by 18 publications

References 39 publications

HepaCAM associates with connexin 43 and enhances its localization in cellular junctions

HepaCAM associates with connexin 43 and enhances its localization in cellular junctions

CLCN2-related leukoencephalopathy: a case report and review of the literature

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

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