1. Zentrum für Molekulare Neurobiologie Hamburg, ZMNH, Universität Hamburg, Falkenried 94, D-20246 Hamburg, Germany

Correspondence to: Thomas J. Jentsch¹ Correspondence and requests for materials should be addressed to T.J.J. (Email: Jentsch@zmnh.uni-hamburg.de).

Abstract

Mutations in ClC-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters^{1, 2}, cause osteopetrosis³ and lysosomal storage disease⁴ in humans and mice. Severe osteopetrosis is also observed with mutations in the OSTM1 gene, which encodes a membrane protein of unknown function⁵. Here we show that both ClC-7 and Ostm1 proteins co-localize in late endosomes and lysosomes of various tissues, as well as in the ruffled border of bone-resorbing osteoclasts. Co-immunoprecipitations show that ClC-7 and Ostm1 form a molecular complex and suggest that Ostm1 is a –subunit of ClC-7. ClC-7 is required for Ostm1 to reach lysosomes, where the highly glycosylated Ostm1 luminal domain is cleaved. Protein but not RNA levels of ClC-7 are greatly reduced in grey-lethal mice, which lack Ostm1, suggesting that the ClC-7–Ostm1 interaction is important for protein stability. As ClC-7 protein levels in Ostm1-deficient tissues and cells, including osteoclasts, are decreased below 10% of normal levels, Ostm1 mutations probably cause osteopetrosis by impairing the acidification of the osteoclast resorption lacuna, which depends on ClC-7 (ref. 3). The finding that grey-lethal mice, just like ClC-7-deficient mice⁴, show lysosomal storage and neurodegeneration in addition to osteopetrosis implies a more general importance for ClC-7–Ostm1 complexes.

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