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| Item Type: | Article |
|---|---|
| Title: | Mutations in CLCN6 as a novel genetic cause of neuronal ceroid lipofuscinosis in patients and a murine model |
| Creators Name: | He, H., Cao, X., He, F., Zhang, W., Wang, X., Peng, P., Xie, C., Yin, F., Li, D., Li, J., Wang, M., Klüssendorf, M., Jentsch, T.J., Stauber, T. and Peng, J. |
| Abstract: | OBJECTIVE: The aim of this study was to explore the pathogenesis of CLCN6-related disease and to assess whether its Cl−/H+-exchange activity is crucial for the biological role of ClC-6. METHODS: We performed whole-exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock-in mouse model of a patient variant (p.E200A) and compared it with a Clcn6−/− mouse model. Additional functional tests were performed with heterologous expression of mutant ClC-6. RESULTS: We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease-causing ClC-6E200A or ClC-6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport-deficient ClC-6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC-6E200A, but not loss of ClC-6 in Clcn6−/− mice, increased lysosomal biogenesis by suppressing mTORC1-TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6−/− brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss. INTERPRETATION: CLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl− transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway. |
| Keywords: | Animal Disease Models, Autophagy, Chloride Channels, Exome Sequencing, Membrane Proteins, Mutation, Neuronal Ceroid-Lipofuscinoses, Animals, Mice |
| Source: | Annals of Neurology |
| ISSN: | 0364-5134 |
| Publisher: | Wiley |
| Volume: | 96 |
| Number: | 3 |
| Page Range: | 608-624 |
| Date: | September 2024 |
| Additional Information: | Erratum in: Ann Neurol 9 Aug 2024. Erratum in: Ann Neurol 28 Aug 2024. |
| Official Publication: | https://doi.org/10.1002/ana.27002 |
| PubMed: | View item in PubMed |
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