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Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation

Item Type:Article
Title:Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation
Creators Name:Weinert, S. and Jabs, S. and Supanchart, C. and Schweizer, M. and Gimber, N. and Richter, M. and Rademann, J. and Stauber, T. and Kornak, U. and Jentsch, T.J.
Abstract:During lysosomal acidification, proton pump currents are thought to be shunted by a Cl(-) channel, tentatively identified as ClC-7. Surprisingly, recent data suggest that ClC-7 rather mediates Cl(-)/H(+)-exchange. We generated mice carrying a point mutation converting ClC-7 into an uncoupled Cl(-) conductor. Despite maintaining lysosomal conductance and normal lysosomal pH, these Clcn7(unc/unc) mice showed lysosomal storage disease like mice lacking ClC-7. However, their osteopetrosis was milder and they lacked a coat color phenotype. Thus, only some roles of ClC-7 Cl(-)/H(+)-exchange can be taken over by a Cl(-) conductance. This conductance was even deleterious in Clcn7(+/unc) mice. Clcn7(-/-) and Clcn7(unc/unc) mice accumulated less Cl(-) in lysosomes than WT mice. Thus, lowered lysosomal chloride may underlie their common phenotypes.
Keywords:Bone and Bones, Cultured Cells, Chloride Channels, Chlorides, Gene Knock-In Techniques, Hippocampus, Hydrogen-Ion Concentration, Lysosomal Storage Diseases, Lysosomes, Membrane Potentials, Membrane Proteins, Mutant Proteins, Osteoclasts, Osteopetrosis, Phenotype, Point Mutation, Protons, Animals, Mice
Publisher:American Association for the Advancement of Science
Page Range:1401-1403
Date:11 June 2010
Official Publication:https://doi.org/10.1126/science.1188072
PubMed:View item in PubMed

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