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We generated and analyzed the first knock\u2010in mouse model of a patient variant (p.E200A) and compared it with a <jats:italic>Clcn6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse model. Additional functional tests were performed with heterologous expression of mutant ClC\u20106.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease\u2010causing ClC\u20106<jats:sup>E200A<\/jats:sup> or ClC\u20106<jats:sup>Y553C<\/jats:sup> 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\u2010deficient ClC\u20106<jats:sup>E267A<\/jats:sup> mutant. <jats:italic>Clcn6<\/jats:italic><jats:sup>E200A\/+<\/jats:sup> mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC\u20106<jats:sup>E200A<\/jats:sup>, but not loss of ClC\u20106 in <jats:italic>Clcn6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, increased lysosomal biogenesis by suppressing mTORC1\u2010TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in <jats:italic>Clcn6<\/jats:italic><jats:sup>E200A\/+<\/jats:sup> brain, while only lipid storage was found in <jats:italic>Clcn6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p><jats:italic>CLCN6<\/jats:italic> is a novel genetic cause of NCLs, highlighting the importance of considering <jats:italic>CLCN6<\/jats:italic> mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl<jats:sup>\u2212<\/jats:sup> transport from H<jats:sup>+<\/jats:sup> countertransport in the E200A mutant has a dominant effect on the autophagic\/lysosomal pathway. ANN NEUROL 2024;96:608\u2013624<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.27002","type":"journal-article","created":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T09:07:23Z","timestamp":1718442443000},"page":"608-624","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mutations in <scp><i>CLCN6<\/i><\/scp> as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in Patients and a Murine Model"],"prefix":"10.1002","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1095-4786","authenticated-orcid":false,"given":"Hailan","family":"He","sequence":"first","affiliation":[{"name":"Department of Pediatrics Xiangya Hospital, Central South University  Changsha China"},{"name":"Clinical Research Center for Children Neurodevelopmental Disabilities of Hunan Province  Changsha China"},{"name":"Institute of Chemistry and Biochemistry Freie Universit\u00e4t Berlin  Berlin 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