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Science. 2010 Jun 11;328(5984):1401-3. doi: 10.1126/science.1188072.

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

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1
Leibniz-Institut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.

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.

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PMID:
20430974
DOI:
10.1126/science.1188072
[Indexed for MEDLINE]
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