期刊
EMBO REPORTS
卷 15, 期 7, 页码 784-791出版社
WILEY
DOI: 10.15252/embr.201438553
关键词
acidification; anion transport; grey-lethal; lysosome; Wnt signalling
资金
- Deutsche Forschungsgemeinschaft [JE164/7, JE164/9, SFB740 TP C5]
- European Research Council (ERC) [294435]
- Prix Louis-Jeantet de Medecine
- European Research Council (ERC) [294435] Funding Source: European Research Council (ERC)
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.
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