Abstract
Chloride channels play important roles in the plasma membrane and in intracellular organelles. Mice deficient for the ubiquitously expressed ClC-7 Cl(-) channel show severe osteopetrosis and retinal degeneration. Although osteoclasts are present in normal numbers, they fail to resorb bone because they cannot acidify the extracellular resorption lacuna. ClC-7 resides in late endosomal and lysosomal compartments. In osteoclasts, it is highly expressed in the ruffled membrane, formed by the fusion of H(+)-ATPase-containing vesicles, that secretes protons into the lacuna. We also identified CLCN7 mutations in a patient with human infantile malignant osteopetrosis. We conclude that ClC-7 provides the chloride conductance required for an efficient proton pumping by the H(+)-ATPase of the osteoclast ruffled membrane.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases
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Animals
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Antigens, CD / metabolism
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Blotting, Northern
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Blotting, Western
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Bone Development / genetics
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Bone Development / physiology*
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Bone Resorption
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Cell Surface Extensions / chemistry
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Cell Surface Extensions / metabolism
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Cells, Cultured
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Chloride Channels / genetics*
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Chloride Channels / metabolism*
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Embryo, Mammalian / anatomy & histology
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Embryo, Mammalian / physiology
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Genes, Reporter
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Humans
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Immunohistochemistry
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In Situ Hybridization
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Integrin beta3
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Mice
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Microscopy, Confocal
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Nerve Degeneration
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Optic Nerve / pathology
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Organelles / chemistry
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Organelles / genetics
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Organelles / metabolism
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Osteoclasts / cytology
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Osteoclasts / metabolism*
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Osteopetrosis / genetics
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Osteopetrosis / pathology
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Osteopetrosis / physiopathology*
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Platelet Membrane Glycoproteins / metabolism
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RNA / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Retina / pathology
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Retinal Degeneration
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Sequence Analysis, DNA
Substances
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Antigens, CD
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CLCN7 protein, human
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Chloride Channels
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Clcn7 protein, mouse
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Integrin beta3
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Platelet Membrane Glycoproteins
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Recombinant Fusion Proteins
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RNA
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Adenosine Triphosphatases