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Abstract

ClC-7 is a ubiquitously expressed chloride channel that is mainly localized in late endosomes and lysosomes. Clcn7 / mice show a severe osteopetrosis (marble bone disease) that becomes apparent shortly after birth (Kornak et al. 2001. Cell. 104:204–215). Although osteoclasts are present in normal numbers, they fail to resorb bone. In osteoclasts, ClC-7 is highly expressed in the ruffled membrane that is formed by the fusion of H -ATPase containing late endosomal vesicles. We could show that chloride ions conducted by ClC-7 provide the necessary countercharge to allow the H -ATPase to efficiently pump large amounts of protons into the resorption lacuna. The murine phenotype closely resembles human infantile malignant osteopetrosis. A screening for mutations in the human gene, CLCN7, was performed in 18 patients suffering from this disease. Two patients were compound heterozygous for a nonsense mutation and two different missense mutations. Two of these mutations lead to a complete loss of the ClC-7 protein in cultured patient fibroblasts corresponding to the loss of ClC-7 in Clcn7 / mice. Recently, mutations in CLCN7 were found to cause also the much milder autosomal dominant form of osteopetrosis (ADOII) (Cleiren et al. 2001. Hum. Mol. Gen. 10:2861–2867). Investigation of primary osteoclasts from several ADOII patients revealed that ClC-7 levels and subcellular localization are not detectably altered. Nevertheless, their resorptive activity is diminished. was increased in the channel open state. This implies that dominant mutations most likely perturb the electrophysiological function of ClC-7 and that changes in the chloride conductance of the ruffled membrane are able to regulate bone resorption and bone density.