Human Molecular Genetics Advance Access published online on August 30, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn269
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Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects
1 CGMM-IDIBELL Gran Via s/n Km. 2,7 08907 L'Hospitalet de Llobregat, Spain 2 Sección de Fisiología, IDIBELL-Universidad de Barcelona, Feixa Llarga s/n, 08907, L'Hospitalet de Llobregat, Spain 3 CIBER de enfermedades raras (CIBERER), U-730 4 CIBER de enfermedades raras (CIBERER), U-750 5 Department of Biochemistry and Molecular Biology and Institute for Research in Biomedicine (IRB), Josep Samitier 1-5. Barcelona, E-08028, Spain 6 Department of Pediatrics/Child Neurology, VU University Medical Center, Amsterdam, he Netherlands 7 Department of Physiology, McGill University, Montreal, Quebec, Canada, H3G 1Y6 8 Department of Cell Biology, Faculty of Biology and Institute for Research in Biomedicine (IRB), Josep Samitier 1-5. Barcelona, E-08028, Spain 9 CIBERDEM, ISCIII 10 CIBER de enfermedades raras (CIBERER), U-731; ISCIII 11 Sección de Genética, Departamento de Ciencias Fisiologicas II, IDIBELL-Universidad de Barcelona, Feixa Llarga s/n, 08907, L'Hospitalet de Llobregat, Spain
* Corresponding author E-mail: restevez{at}ub.edu (RE)
Received July 24, 2008; Revised August 28, 2008; Accepted August 28, 2008
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy, most often caused by mutations in the MLC1 gene. MLC1 is an oligomeric plasma membrane protein of unknown function expressed mainly in glial cells and neurons. Most disease-causing missense mutations dramatically reduced the total and plasma membrane MLC1 expression levels in Xenopus oocytes and mammalian cells. The impaired expression of the mutants was verified in primary cultures of rat astrocytes, as well as human monocytes, cell types that endogenously express MLC1, demonstrating the relevance of the tissue culture models. Using a combination of biochemical, pharmacological and imaging methods, we also demonstrated that increased endoplasmatic reticulum-associated degradation (ERAD) and endo-lysosomal associated degradation (ELAD) can contribute to the cell surface expression defect of the mutants. Based on these results, we suggest that MLC1 mutations reduce protein levels in vivo. Since the expression defect of the mutants could be rescued by exposing the mutant-protein expressing cells to low temperature and glycerol, a chemical chaperone, we propose that MLC belongs to the class of conformational diseases. Therefore, we suggest the use of pharmacological strategies that improve MLC1 expression to treat MLC patients.
& These authors contributed equally to this study
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