Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions

EMBO Rep. 2014 Jul;15(7):784-91. doi: 10.15252/embr.201438553. Epub 2014 May 12.


Loss of the lysosomal ClC-7/Ostm1 2Cl(-)/H(+) exchanger causes lysosomal storage disease and osteopetrosis in humans and additionally changes fur colour in mice. Its conversion into a Cl(-) conductance in Clcn7(unc/unc) mice entails similarly severe lysosomal storage, but less severe osteopetrosis and no change in fur colour. To elucidate the basis for these phenotypical differences, we generated Clcn7(td/td) mice expressing an ion transport-deficient mutant. Their osteopetrosis was as severe as in Clcn7(-/-) mice, suggesting that the electric shunt provided by ClC-7(unc) can partially rescue osteoclast function. The normal coat colour of Clcn7(td/td) mice and their less severe neurodegeneration suggested that the ClC-7 protein, even when lacking measurable ion transport activity, is sufficient for hair pigmentation and that the conductance of ClC-7(unc) is harmful for neurons. Our in vivo structure-function analysis of ClC-7 reveals that both protein-protein interactions and ion transport must be considered in the pathogenesis of ClC-7-related diseases.

Keywords: Wnt signalling; acidification; anion transport; grey‐lethal; lysosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Biological Transport
  • CA3 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / pathology
  • Fibroblasts / metabolism
  • Genotype
  • Hair Color / genetics
  • Homeostasis
  • Ions / metabolism
  • Lysosomes / metabolism
  • Melanocytes / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Neurons / pathology
  • Osteopetrosis / genetics
  • Osteopetrosis / metabolism
  • Osteopetrosis / pathology
  • Phenotype
  • Wnt Signaling Pathway


  • Ions
  • Membrane Proteins
  • OSTM1 protein, mouse