Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man


  • U. Kornak
  • D. Kasper
  • M.R. Boesl
  • E. Kaiser
  • M. Schweizer
  • A. Schulz
  • W. Friedrich
  • G. Delling
  • T.J. Jentsch


  • Cell


  • Cell 104 (2): 205-215


  • 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.