title: Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation.
abstract: During lysosomal acidification, proton-pump currents are thought to be shunted by a chloride ion (Cl-) channel, tentatively identified as ClC-7. Surprisingly, recent data suggest that ClC-7 instead mediates Cl-/proton (H+) exchange. We generated mice carrying a point mutation converting ClC-7 into an uncoupled (unc) 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 did wild-type mice. Thus, lowered lysosomal chloride may underlie their common phenotypes.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weinert
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jabs
authors.forename: Chayarop
authors.initials: C
authors.lastname: Supanchart
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Niclas
authors.initials: N
authors.lastname: Gimber
authors.forename: Martin
authors.initials: M
authors.lastname: Richter
authors.forename: Jörg
authors.initials: J
authors.lastname: Rademann
authors.forename: Tobias
authors.initials: T
authors.lastname: Stauber
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006200:Hair Color; D006624:Hippocampus / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D016464:Lysosomal Storage Diseases / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010022:Osteopetrosis / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017354:Point Mutation; D011522:Protons
chemical_list: D018118:Chloride Channels; D002712:Chlorides; C490803:Clcn7 protein, mouse; D008565:Membrane Proteins; D050505:Mutant Proteins; C509143:OSTM1 protein, mouse; D011522:Protons