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

During lysosomal acidification, proton-pump currents are thought to be shunted by a chloride ion (CD channel, tentatively identified as ClC-7. Surprisingly, recent data suggest that ClC-7 instead mediates G7proton (H+) exchange. We generated mice carrying a point mutation converting ClC-7 into an uncoupled (unc) 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 Clcn+/unc mice. Clcn7-/- and Clcn7un/unc mice accumulated less Cl- in lysosomes than did wild-type mice. Thus, lowered lysosomal chloride may underlie their common phenotypes. [ABSTRACT FROM AUTHOR]