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Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6

Item Type:Article
Title:Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6
Creators Name:Poet, M. and Kornak, U. and Schweizer, M. and Zdebik, A.A. and Scheel, O. and Hoelter, S. and Wurst, W. and Schmitt, A. and Fuhrmann, J.C. and Planells-Cases, R. and Mole, S.E. and Huebner, C.A. and Jentsch, T.J.
Abstract:Mammalian CLC proteins function as Cl(-) channels or as electrogenic Cl(-)/H(+) exchangers and are present in the plasma membrane and intracellular vesicles. We now show that the ClC-6 protein is almost exclusively expressed in neurons of the central and peripheral nervous systems, with a particularly high expression in dorsal root ganglia. ClC-6 colocalized with markers for late endosomes in neuronal cell bodies. The disruption of ClC-6 in mice reduced their pain sensitivity and caused moderate behavioral abnormalities. Neuronal tissues showed autofluorescence at initial axon segments. At these sites, electron microscopy revealed electron-dense storage material that caused a pathological enlargement of proximal axons. These deposits were positive for several lysosomal proteins and other marker proteins typical for neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. However, the lysosomal pH of Clcn6(-/-) neurons appeared normal. CLCN6 is a candidate gene for mild forms of human NCL. Analysis of 75 NCL patients identified ClC-6 amino acid exchanges in two patients but failed to prove a causative role of CLCN6 in that disease.
Keywords:Acidification, Anion transport, Batten disease, Channelopathy, Kuf's disease, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:103
Number:37
Page Range:13854-13859
Date:12 September 2006
Official Publication:https://doi.org/10.1073/pnas.0606137103
PubMed:View item in PubMed

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