Lysosomal Pathology and Osteopetrosis upon Loss of H+-Driven Lysosomal Cl Accumulation

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Science  29 Apr 2010:
DOI: 10.1126/science.1188072


During lysosomal acidification, proton pump currents are thought to be shunted by a Cl channel, tentatively identified as ClC-7. Surprisingly, recent data suggest that ClC-7 rather mediates Cl/H+-exchange. We generated mice carrying a point mutation converting ClC-7 into an uncoupled Cl conductor. Despite maintaining lysosomal conductance and normal lysosomal pH, these Clcn7unc/unc mice showed lysosomal storage disease like mice lacking ClC-7. However, their osteopetrosis was milder and they lacked a coat color phenotype. Thus, only some roles of ClC-7 Cl/H+-exchange can be taken over by a Cl conductance. This conductance was even deleterious in Clcn7+/unc mice. Clcn7–/– and Clcn7unc/unc mice accumulated less Cl in lysosomes than WT mice. Thus, lowered lysosomal chloride may underlie their common phenotypes.