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Transport activity and presence of ClC‐7/Ostm1 complex account for different cellular functions
Author(s) -
Weinert Stefanie,
Jabs Sabrina,
Hohensee Svea,
Chan Wing Lee,
Kornak Uwe,
Jentsch Thomas J
Publication year - 2014
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201438553
Subject(s) - osteopetrosis , microbiology and biotechnology , mutant , transport protein , neurodegeneration , biology , pathogenesis , phenotype , chemistry , biochemistry , immunology , disease , medicine , gene
Loss of the lysosomal ClC ‐7/ O stm1 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.