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| Item Type: | Article |
|---|---|
| Title: | Mutations in CLCN6 as a novel genetic cause of neuronal ceroid lipofuscinosis |
| 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-6(v) or ClC-6(Y553C) 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-6(E267A) mutant. Clcn6(E200A/+) mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC-6(E200A), 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 Clcn6(E200A/+) 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. ANN NEUROL 2024. |
| Keywords: | Animals, Mice |
| Source: | Annals of Neurology |
| ISSN: | 0364-5134 |
| Publisher: | Wiley |
| Date: | 15 June 2024 |
| Official Publication: | https://doi.org/10.1002/ana.27002 |
| PubMed: | View item in PubMed |
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