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Journal Article

Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation.

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons50391

Kornak,  U.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Weinert, S., Jabs, S., Supanchart, C., Schweizer, M., Gimber, N., Richter, M., et al. (2010). Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation. Science, 328(5984), 1401-1403. doi:10.1126/science.1188072.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-7AD6-D
Abstract
During lysosomal acidification, proton-pump currents are thought to be shunted by a chloride ion (Cl-) channel, tentatively identified as ClC-7. Surprisingly, recent data suggest that ClC-7 instead mediates Cl-/proton (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 Clcn7(unc/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 Clcn7(unc/unc) mice accumulated less Cl- in lysosomes than did wild-type mice. Thus, lowered lysosomal chloride may underlie their common phenotypes.