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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / pathology
  • Cells, Cultured
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Chlorides / metabolism*
  • Gene Knock-In Techniques
  • Hair Color
  • Hippocampus / pathology
  • Hydrogen-Ion Concentration
  • Lysosomal Storage Diseases / metabolism
  • Lysosomal Storage Diseases / pathology
  • Lysosomes / metabolism*
  • Membrane Potentials
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mutant Proteins / metabolism
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Osteopetrosis / metabolism*
  • Osteopetrosis / pathology
  • Phenotype
  • Point Mutation
  • Protons*

Substances

  • Chloride Channels
  • Chlorides
  • Clcn7 protein, mouse
  • Membrane Proteins
  • Mutant Proteins
  • OSTM1 protein, mouse
  • Protons