title: Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions.
abstract: Loss of the lysosomal ClC-7/Ostm1 2Cl(-)/H(+) exchanger causes lysosomal storage disease and osteopetrosis in humans and additionally changes fur colour in mice. Its conversion into a Cl(-) conductance in Clcn7(unc/unc) mice entails similarly severe lysosomal storage, but less severe osteopetrosis and no change in fur colour. To elucidate the basis for these phenotypical differences, we generated Clcn7(td/td) mice expressing an ion transport-deficient mutant. Their osteopetrosis was as severe as in Clcn7(-/-) mice, suggesting that the electric shunt provided by ClC-7(unc) can partially rescue osteoclast function. The normal coat colour of Clcn7(td/td) mice and their less severe neurodegeneration suggested that the ClC-7 protein, even when lacking measurable ion transport activity, is sufficient for hair pigmentation and that the conductance of ClC-7(unc) is harmful for neurons. Our in vivo structure-function analysis of ClC-7 reveals that both protein-protein interactions and ion transport must be considered in the pathogenesis of ClC-7-related diseases.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weinert
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jabs
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.
authors.forename: Svea
authors.initials: S
authors.lastname: Hohensee
authors.affiliation: Institut für Humangenetik, Charité Universitätsmedizin Berlin, Berlin, Germany Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
authors.forename: Wing Lee
authors.initials: WL
authors.lastname: Chan
authors.affiliation: Institut für Humangenetik, Charité Universitätsmedizin Berlin, Berlin, Germany Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany Neurocure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany jentsch@fmp-berlin.de.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000483:Alleles; D000818:Animals; D001692:Biological Transport; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006200:Hair Color / Q000235:genetics; D006706:Homeostasis; D007477:Ions / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D060449:Wnt Signaling Pathway
chemical_list: D007477:Ions; D008565:Membrane Proteins; C509143:OSTM1 protein, mouse
keywords: Wnt signalling; acidification; anion transport; grey‐lethal; lysosome