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1000
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Abstract/Summary
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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 Clcn7unc/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 Clcn7td/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‐7unc can partially rescue osteoclast function. The normal coat colour of Clcn7td/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‐7unc 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.
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