Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans

Hum Mol Genet. 2014 Oct 1;23(19):5069-86. doi: 10.1093/hmg/ddu231. Epub 2014 May 12.


Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a leukodystrophy characterized by myelin vacuolization and caused by mutations in MLC1 or GLIALCAM. Patients with recessive mutations in either MLC1 or GLIALCAM show the same clinical phenotype. It has been shown that GLIALCAM is necessary for the correct targeting of MLC1 to the membrane at cell junctions, but its own localization was independent of MLC1 in vitro. However, recent studies in Mlc1(-/-) mice have shown that GlialCAM is mislocalized in glial cells. In order to investigate whether the relationship between Mlc1 and GlialCAM is species-specific, we first identified MLC-related genes in zebrafish and generated an mlc1(-/-) zebrafish. We have characterized mlc1(-/-) zebrafish both functionally and histologically and compared the phenotype with that of the Mlc1(-/-) mice. In mlc1(-/-) zebrafish, as in Mlc1(-/-) mice, Glialcam is mislocalized. Re-examination of a brain biopsy from an MLC patient indicates that GLIALCAM is also mislocalized in Bergmann glia in the cerebellum. In vitro, impaired localization of GlialCAM was observed in astrocyte cultures from Mlc1(-/-) mouse only in the presence of elevated potassium levels, which mimics neuronal activity. In summary, here we demonstrate an evolutionary conserved role for MLC1 in regulating glial surface levels of GLIALCAM, and this interrelationship explains why patients with mutations in either gene (MLC1 or GLIALCAM) share the same clinical phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Astrocytes / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Cell Cycle Proteins
  • Cell Line
  • Cell Membrane / metabolism
  • Cysts / genetics
  • Cysts / metabolism*
  • Disease Models, Animal
  • Ependyma / cytology
  • Ependyma / metabolism
  • Ependyma / ultrastructure
  • Gene Expression
  • Genotype
  • Hereditary Central Nervous System Demyelinating Diseases / genetics
  • Hereditary Central Nervous System Demyelinating Diseases / metabolism*
  • Humans
  • Intercellular Junctions / metabolism
  • Intercellular Junctions / ultrastructure
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation
  • Neuroglia / metabolism*
  • Phenotype
  • Protein Transport
  • Proteins / genetics
  • Proteins / metabolism*
  • Retina / metabolism
  • Voltage-Dependent Anion Channels / metabolism
  • Zebrafish / genetics
  • Zebrafish / metabolism


  • Cell Cycle Proteins
  • HEPACAM protein, human
  • MLC1 protein, human
  • Membrane Proteins
  • Proteins
  • Voltage-Dependent Anion Channels

Supplementary concepts

  • Megalencephalic leukoencephalopathy with subcortical cysts