New advances in the understanding of the pathophysiology of megalencephalic leukoencephalopathy (MLC) minority brain disease

  • MLC is a genetic disease caused by the mutation of the MLC1 and GLIALCAM genes.
  • Two recent articles with the participation of a research group from IDIBELL, the University of Barcelona, and CIBERER describe different protein interactions of MLC1 and GlialCAM that could regulate neuronal development and activity.
Raul Estevez_2021

MLC is a genetic disease that affects the myelin of the central nervous system, the white matter. It is a type of leukodystrophy characterized by megalencephaly caused by an increase in brain water content. Patients have epilepsy, ataxia, and mild cognitive problems. This disease is caused by mutations in the MLC1 and GLIALCAM genes, which code for two membrane proteins of unknown function. Unfortunately, there is still no treatment.

A research group from IDIBELL, the University of Barcelona, ​​the Institute of Neurosciences of the UB, and the CIBERER, has published two articles that advance the understanding of the pathophysiology of MLC. These works describe several proteins that interact with GlialCAM, the mutated gene in patients with MLC.

First, an article published in the journal Neuron, led by Cagli Eroglu from Duke University, and in which Dr. Estévez’s team has participated, describes that the lack of the GlialCAM protein affects the location of the connexin 43, a protein that forms a strong union between astrocytes, the most abundant cells in the nervous system that support neurons. These alterations affect the structural organization of astrocytes and the couplings between them, affecting the balance between excitation and inhibition.

On the other hand, Dr. Estévez’s group has led a study published in the journal Human Molecular Genetics in which describes the proteins that interact with GlialCAM. Among them, different transporters, ion channels, and proteins related to adhesion and signaling have been described, for example, orphan receptors coupled to G proteins: GPR37L1 and GPRC5B. The researchers propose that GlialCAM associates with various cell membrane proteins to recruit and regulate their function, playing an important role in cell signaling.

Both works have jointly suggested that the function of the GlialCAM and MLC1 proteins would be to organize protein networks at the junctions of astrocytes, regulating neuronal development and activity. An astrocytic functional defect is implicated as a direct cause of neuropathology.



The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).

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