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


  • S. Weinert
  • S. Jabs
  • C. Supanchart
  • M. Schweizer
  • N. Gimber
  • M. Richter
  • J. Rademann
  • T. Stauber
  • U. Kornak
  • T.J. Jentsch


  • Science


  • Science 328 (5984): 1401-1403


  • 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 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 WT mice. Thus, lowered lysosomal chloride may underlie their common phenotypes.