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

Cell. 2001 Jan 26;104(2):205-15. doi: 10.1016/s0092-8674(01)00206-9.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases
  • Animals
  • Antigens, CD / metabolism
  • Blotting, Northern
  • Blotting, Western
  • Bone Development / genetics
  • Bone Development / physiology*
  • Bone Resorption
  • Cell Surface Extensions / chemistry
  • Cell Surface Extensions / metabolism
  • Cells, Cultured
  • Chloride Channels / genetics*
  • Chloride Channels / metabolism*
  • Embryo, Mammalian / anatomy & histology
  • Embryo, Mammalian / physiology
  • Genes, Reporter
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Integrin beta3
  • Mice
  • Microscopy, Confocal
  • Nerve Degeneration
  • Optic Nerve / pathology
  • Organelles / chemistry
  • Organelles / genetics
  • Organelles / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / metabolism*
  • Osteopetrosis / genetics
  • Osteopetrosis / pathology
  • Osteopetrosis / physiopathology*
  • Platelet Membrane Glycoproteins / metabolism
  • RNA / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Retina / pathology
  • Retinal Degeneration
  • Sequence Analysis, DNA

Substances

  • Antigens, CD
  • CLCN7 protein, human
  • Chloride Channels
  • Clcn7 protein, mouse
  • Integrin beta3
  • Platelet Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • RNA
  • Adenosine Triphosphatases