title: Expanding the spectrum of megalencephalic leukoencephalopathy with subcortical cysts in two patients with GLIALCAM mutations.
abstract: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a heterogeneous neurodegenerative leukodystrophy caused by recessive mutations in MLC1 or GLIALCAM (types MLC1 and MLC2A) of by dominant mutations in GLIALCAM (MLC2B). GlialCAM functions as an auxiliary subunit of both MLC1 and ClC-2 chloride channel, increasing and modifying the function of the latter. Dominant mutations in GLIALCAM cause transient features of MLC but lacks clinical deterioration. Most recessive and dominant mutations in GLIALCAM studied so far affect the targeting of GlialCAM and its associated subunits. Here, we have investigated two patients with MLC2. The first patient has MLC2B disease, as shown by the improvement in MRI and clinical parameters. In this case, we identified a novel GLIALCAM mutation (p.Q56P) which affected the localization of GlialCAM and its associated subunits, however activating ClC-2 function as the wild-type protein. The second patient has MLC2A disease, as indicated by the lack of clinical improvement, even though, interestingly, the MRI of this patient shows a partial improvement. In this case, we found a recessive mode of inheritance, as the patient harbors two compound heterozygous mutations in GLIALCAM. One of them introduces a stop codon (p.Q56X), whereas the second mutation is a missense mutation (p.R73W), for which we could not identify any trafficking defect or an altered functional effect on ClC-2 in vitro.
authors.affiliation: Sección de Fisiología, Departamento de Ciencias Fisiológicas II, Universidad de Barcelona, Barcelona, Spain.
authors.forename: Tanit
authors.initials: T
authors.lastname: Arnedo
authors.forename: Chiara
authors.initials: C
authors.lastname: Aiello
authors.forename: Elena
authors.initials: E
authors.lastname: Jeworutzki
authors.forename: Maria Lisa
authors.initials: ML
authors.lastname: Dentici
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Alessandro
authors.initials: A
authors.lastname: Simonati
authors.forename: Michael
authors.initials: M
authors.lastname: Pusch
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Raúl
authors.initials: R
authors.lastname: Estévez
mesh_terms: D000293:Adolescent; D001921:Brain / Q000473:pathology; D000090007:CLC-2 Chloride Channels; D018797:Cell Cycle Proteins; D002648:Child; D018118:Chloride Channels / Q000235:genetics; D018388:Codon, Terminator; D003560:Cysts / Q000235:genetics*; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D005808:Genes, Recessive; D057809:HEK293 Cells; D006367:HeLa Cells; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation; D018408:Patch-Clamp Techniques; D010641:Phenotype; D017433:Protein Structure, Secondary; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D000090007:CLC-2 Chloride Channels; D018797:Cell Cycle Proteins; D018118:Chloride Channels; D018388:Codon, Terminator; D018076:DNA, Complementary; C487620:HEPACAM protein, human; D011506:Proteins