Referenced in: none

Automatically associated channels: ClC3 , ClC4

Title: CLC-3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis.

Authors: Momono Yoshikawa, Shinichi Uchida, Junji Ezaki, Tatemitsu Rai, Atsushi Hayama, Katsuki Kobayashi, Yujiro Kida, Masaki Noda, Masato Koike, Yasuo Uchiyama, Fumiaki Marumo, Eiki Kominami, Sei Sasaki

Journal, date & volume: Genes Cells, 2002 Jun , 7, 597-605

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12059962

Abstract
CLC-3 is a member of the CLC chloride channel family and is widely expressed in mammalian tissues. To determine the physiological role of CLC-3, we generated CLC-3-deficient mice (Clcn3-/- ) by targeted gene disruption.Together with developmental retardation and higher mortality, the Clcn3-/- mice showed neurological manifestations such as blindness, motor coordination deficit, and spontaneous hyperlocomotion. In histological analysis, the Clcn3-/- mice showed a pattern of progressive degeneration of the retina, hippocampus and ileal mucosa, which resembled the phenotype observed in cathepsin D knockout mice. The defect of cathepsin D results in a lysosomal accumulation of ceroid lipofuscin containing the mitochondrial F1F0 ATPase subunit c. In immunohistochemistry and Western blot analysis, we found that the subunit c was heavily accumulated in the lysosome of Clcn3-/- mice. Furthermore, we detected an elevation in the endosomal pH of the Clcn3-/- mice.These results indicated that the neurodegeneration observed in the Clcn3-/- mice was caused by an abnormality in the machinery which degrades the cellular protein and was associated with the phenotype of neuronal ceroid lipofuscinosis (NCL). The elevated endosomal pH could be an important factor in the pathogenesis of NCL.