Referenced in: none

Automatically associated channels: ClC4 , ClC6

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

Authors: Mallorie Poet, Uwe Kornak, Michaela Schweizer, Anselm A Zdebik, Olaf Scheel, Sabine Hoelter, Wolfgang Wurst, Anja Schmitt, Jens C Fuhrmann, Rosa Planells-Cases, Sara E Mole, Christian A Hübner, Thomas J Jentsch

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2006 Sep 12 , 103, 13854-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16950870

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.