Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions

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. Synopsis Comparison of ClC‐7‐deficient, ClC‐7 unc and ClC‐7 td mice suggests that a pure Cl − conductance partially rescues the lack of Cl − /H + exchange in osteoclasts, whereas normal pigmentation requires ClC‐7 protein interactions, but not ClC‐7 ion transport activity. The study also shows that the ion transport‐deficient ClC‐7 td /Ostm1 complex was beneficial for neurons, whereas the Cl − conductance of ClC‐7 unc may have detrimental effects on CNS neurons. Loss of ClC‐7/Ostm1 Cl − /H + exchange can be partially compensated in osteoclasts by a mutant exhibiting an uncoupled Cl − conductance. The transport‐deficient ClC‐7 td /Ostm1 complex is sufficient for normal hair pigmentation and attenuates lysosomal storage and neurodegeneration. ClC‐7 unc /Ostm1, but not ClC‐7 td /Ostm1, has a negative effect on neuronal survival. Graphical Abstract Comparison of ClC‐7‐deficient, ClC‐7 unc and ClC‐7 td mice suggests that a pure Cl − conductance partially rescues the lack of Cl − /H + exchange in osteoclasts, whereas normal pigmentation requires ClC‐7 protein interactions, but not ClC‐7 ion transport activity. The study also shows that the ion transport‐deficient ClC‐7 td /Ostm1 complex was beneficial for neurons, whereas the Cl − conductance of ClC‐7 unc may have detrimental effects on CNS neurons.