Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.
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.
Kornak
U
U
Zentrum für Molekulare Neurobiologie Hamburg, ZMNH, Universität Hamburg, D-20246, Hamburg, Germany.
Kasper
D
D
Bösl
M R
MR
Kaiser
E
E
Schweizer
M
M
Schulz
A
A
Friedrich
W
W
Delling
G
G
Jentsch
T J
TJ
D000251:Adenosine Triphosphatases; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D001846:Bone Development / Q000235:genetics / Q000502:physiology*; D001862:Bone Resorption; D022081:Cell Surface Extensions / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D039661:Integrin beta3; D051379:Mice; D018613:Microscopy, Confocal; D009410:Nerve Degeneration; D009900:Optic Nerve / Q000473:pathology; D015388:Organelles / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010022:Osteopetrosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration; D017422:Sequence Analysis, DNA
D015703:Antigens, CD; C097540:CLCN7 protein, human; D018118:Chloride Channels; C490803:Clcn7 protein, mouse; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D012313:RNA; D000251:Adenosine Triphosphatases