Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents

Xavier Capdevila-Nortes, Tania López-Hernández, Pirjo M. Apaja, Miguel López de Heredia, Sònia Sirisi, Gerard Callejo, Tanit Arnedo, Virginia Nunes, Gergely L. Lukacs, Xavier Gasull, Raúl Estévez

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


Megalencephalic leukoencephalopathywith subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM genes and is associated with myelin and astrocyte vacuolation. It has beensuggested thatMLCis caused byimpaired cell volume regulation as a result of defective activation of astrocytic volume-regulated anion currents (VRAC). GlialCAM brings MLC1 and the ClC-2 Cl- channel to cell-cell junctions, even though the role of ClC-2 in MLC disease remains incompletely understood. To gain insights into the biological role of GlialCAM in the pathogenesis of MLC disease, here we analyzed the gain- and lossof- function phenotypes of GlialCAM in Hela cells and primary astrocytes, focusing on its interaction with the MLC1 protein. Unexpectedly, GlialCAM ablation provoked intracellular accumulation and reduced expression of MLC1 at the plasma membrane. Conversely, over-expression of GlialCAM increased the cellular stability of mutant MLC1 variants. Reduction in GlialCAM expression resulted in defective activation ofVRAC and augmented vacuolation, phenocopying MLC1 mutations. Importantly, over-expression of GlialCAM together with MLC1 containingMLC-related mutationswasable to reactivateVRACcurrentsandto reverse thevacuolationcausedin the presence of mutant MLC1. These results indicate a previously unrecognized role of GlialCAM in facilitating the biosynthetic maturation and cell surface expression of MLC1, and suggest that pharmacological strategies aimed to increase surface expression of MLC1 and/or VRAC activity may be beneficial for MLC patients.

Original languageEnglish
Article numberddt290
Pages (from-to)4405-4416
Number of pages12
JournalHuman molecular genetics
Issue number21
Publication statusPublished or Issued - Nov 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this