Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

The Netherlands
Megalencephalic leukoencephalopathy with subcortical cysts: from molecular basis to search for therapy

Project Coordinator

IDIBELL Ciencias Fisiologiques II
L'Hospitalet de Llobregat


Huibert Mansvelder VU University Medical Center Integrative Neurophysiology Amsterdam, The Netherlands
Marjo S. van der Knaap VU University Medical Center Child Neurology Amsterdam, The Netherlands
Mark Verheijen Center for Neurogenomics and Cognitive Research Molecular and Cellular Neurobiology Amsterdam, The Netherlands

Publications of the MLC-team project

Major results of the project

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, genetic brain disease, clinically characterized by early-onset macrocephaly and after a few years slow deterioration of motor functions, epilepsy and mental decline. In MLC, the cerebral myelin is vacuolated, causing white matter swelling. MLC1 is the first gene demonstrated to be involved in this disease, and it encodes a transmembrane protein of unknown function mainly expressed in astroglial processes. MLC1 mutations reduce MLC1 protein levels. At the beginning of the project, there was no insight into the pathophysiology of MLC and no specific therapy was available. Furthermore, genetic studies had demonstrated that there were other unidentified disease MLC genes.
The general objective of the project was to gain insights into the disease mechanism of MLC in order to find openings for treatment. In order to achieve this objective, we proposed a multidisciplinary approach. Thus, the planned experiments comprise the characterization of animal models of MLC disease (mice and zebrafish, created by inactivation of the MLC1 gene), the analysis of cells with decreased MLC1 expression and a search for new MLC disease genes by genetic linkage or analysis of the MLC1 protein interactome.
We expected that, based on the outcome of the research proposed, we could be able to design screening studies aimed at identifying molecules that could be used for therapy, and they could be tested in our animal models.
With these objectives in mind, our collaborative team identified the second gene of MLC disease, GLIALCAM, which has the role to be a MLC1 subunit, and their interaction is needed for MLC1 proper expression at the membrane in astrocyte-astrocyte junctions. Furthermore, we discovered that in MLC two types of chloride channels are affected. In one hand, GlialCAM had been identified as a ClC-2 auxiliary subunit and in vivo studies in MLC animal models have shown that the chloride channel ClC-2 is mislocalized in astrocytes and oligodendrocytes. On the other hand, electrophysiological measurements from lymphoblast obtained from patients, astrocytes depleted of MLC1 or GlialCAM by RNA interference or astrocytes from the Mlc1-/- mice have shown that the activation of volume-regulated anion currents (VRAC) is impaired. The VRAC activity is involved in cellular osmotic response and failure of its activity may lead to the vacuolization observed in astrocytes.
Thus, we have moved from a lack of knowledge in the pathophysiology of MLC to get the first insights into what physiological process are affected. We envisage that the next years of research in MLC will result in finding exciting molecular details which will allow understanding the exact role of MLC1/GlialCAM in the regulation of chloride fluxes by glial cells and hopefully will provide novel therapies for MLC.

E-Rare 2012 - Created by Toussaint Biger