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Poët, M.* ; Kornak, U.* ; Schweizer, M.* ; Zdebik, A.A.* ; Scheel, O.* ; Hölter, S.M. ; Wurst, W. ; Schmitt, A.* ; Fuhrmann, J.C.* ; Planells-Cases, R.* ; Mole, S.E.* ; Hübner, C.A.* ; Jentsch, T.J.*

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

Proc. Natl. Acad. Sci. U.S.A. 103, 13854-13859 (2006)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords acidification; anion transport; Batten disease; channelopathy; Kuf's disease; CLC CL-CHANNELS; CEROID-LIPOFUSCINOSIS; DENTS-DISEASE; INTRACELLULAR LOCATION; MOLECULAR-BASIS; CBS DOMAINS; MOUSE; LEADS; MODEL; MICE
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Quellenangaben Volume: 103, Issue: 37, Pages: 13854-13859 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Reviewing status Peer reviewed