ArticleMolecular neurobiology2021
West Syndrome Caused By a Chloride/Proton Exchange-Uncoupling CLCN6 Mutation Related to Autophagic-Lysosomal Dysfunction.
Article in Molecular neurobiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- Mitochondrial and lysosomal dysfunctions might be involved in the pathogenesis of the CACNA1A-related neurodevelopmental disorders according to in vitro studies.Biological research · 2025Article
- Infantile Spasms (West Syndrome): Integrating Genetic, Neurotrophic, and Hormonal Mechanisms Toward Precision Therapy.Medicina (Kaunas, Lithuania) · 2025Review
- Role of voltage-gated chloride channels in epilepsy: current insights and future directions.Frontiers in pharmacology · 2025Review
- Pathological Functions of Lysosomal Ion Channels in the Central Nervous System.International journal of molecular sciences · 2024Review
- Molecular basis of ClC-6 function and its impairment in human disease.Science advances · 2023Article
- Biophysical Aspects of Neurodegenerative and Neurodevelopmental Disorders Involving Endo-/Lysosomal CLC ClLife (Basel, Switzerland) · 2023Review
- Molecular Abnormalities in BTBR Mice and Their Relevance to Schizophrenia and Autism Spectrum Disorders: An Overview of Transcriptomic and Proteomic Studies.Biomedicines · 2023Article
- Vesicular CLC chloride/proton exchangers in health and diseases.Frontiers in pharmacology · 2023Review
- Correlation of age of onset and clinical severity in Niemann-Pick disease type C1 with lysosomal abnormalities and gene expression.Scientific reports · 2022Article
- The Role of the Lysosomal ClCells · 2022Review
- ClC-3 regulates the excitability of nociceptive neurons and is involved in inflammatory processes within the spinal sensory pathway.Frontiers in cellular neuroscience · 2022Article
- Application of Metabolomics in the Study of Starvation-Induced Autophagy inJournal of fungi (Basel, Switzerland) · 2021Article
- Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders.American journal of human genetics · 2021Article
- Neurodegeneration Upon Dysfunction of Endosomal/Lysosomal CLC Chloride Transporters.Frontiers in cell and developmental biology · 2021Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Vesicular chloride/proton exchangers of the CLC family are critically involved in the function of the endosomal-lysosomal pathway. Their dysfunction leads to severe disorders including intellectual disability and epilepsy for ClC-4, Dent's disease for ClC-5, and lysosomal storage disease and osteopetrosis for ClC-7. Here, we report a de novo variant p.Glu200Ala (p.E200A; c.599A>C) of the late endosomal ClC-6, encoded by CLCN6, in a patient with West syndrome (WS), severe developmental delay, autism, movement disorder, microcephaly, facial dysmorphism, and visual impairment. Mutation of this conserved glutamate uncouples chloride transport from proton antiport by ClC-6. This affects organellar ion homeostasis and was shown to be deleterious for other CLCs. In this study, we found that upon heterologous expression, the ClC-6 E200A variant caused autophagosome accumulation and impaired the clearance of autophagosomes by blocking autophagosome-lysosome fusion. Our study provides clinical and functional support for an association between CLCN6 variants and WS. Our findings also provide novel insights into the molecular mechanisms underlying the pathogenesis of WS, suggesting an involvement of autophagic-lysosomal dysfunction.
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Registered trials
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