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Gene Review

CLCN7  -  chloride channel, voltage-sensitive 7

Homo sapiens

Synonyms: CLC-7, CLC7, Chloride channel 7 alpha subunit, Chloride channel protein 7, ClC-7, ...
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Disease relevance of CLCN7

  • We also identified CLCN7 mutations in a patient with human infantile malignant osteopetrosis [1].
  • CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects [2].
  • CONCLUSION: We observed a significant association of CLCN7 polymorphisms with the variance of BMD and bone resorption marker levels in postmenopausal women and with the variability of the ADOII phenotype [3].
  • Mice deficient for the ubiquitously expressed ClC-7 Cl(-) channel show severe osteopetrosis and retinal degeneration [1].
  • Loss-of-function mutations in the endosomal protein ClC-5 impair renal endocytosis and lead to kidney stones, whereas loss of function of the endosomal/lysosomal protein ClC-7 entails osteopetrosis and lysosomal storage disease [4].
  • ADO caused by mutations in the CLCN7 gene is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, and occasional bone marrow failure [5].

High impact information on CLCN7


Chemical compound and disease context of CLCN7


Biological context of CLCN7

  • MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects [2].
  • Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women [2].
  • We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age [2].
  • Comparison of the genomic organization of CLCN6 and CLCN7 genes shows that just eight introns are located at corresponding cDNA positions [8].
  • The Clcn7 promoter was transactivated by coexpression of MITF in reporter gene assays [9].

Anatomical context of CLCN7

  • In the majority of cases, mutations in either of two human genes cause this fatal disorder: TCIRG1, encoding a subunit of the osteoclast H(+)-ATPase, and the voltage-gated chloride channel gene CLCN7 [10].
  • Both ClC-6 and ClC-7 cannot be expressed as chloride channels in Xenopus oocytes, either singly or in combination [11].
  • Screening 50 different human tissues showed a broad expression for CLIC1 and a restricted immunoreactivity for ClC-7, appearing mainly in osteoclasts, ovaries, appendix, and Purkinje cells [12].
  • MATERIALS AND METHODS: We isolated CD14+ monocytes from human peripheral blood from either controls or patients with autosomal dominant osteopetrosis type II (ADOII) caused by defective ClC-7 function and cultured them in the presence of RANKL and macrophage-colony stimulating factor (M-CSF) to generate osteoclasts [13].

Associations of CLCN7 with chemical compounds

  • ClC-6 has a highly conserved glycosylation site between transmembrane domains D8 and D9, while ClC-7 is the only known eukaryotic ClC protein which lacks this site [11].

Other interactions of CLCN7

  • The expression of clcn7 and ostm1 in osteoclasts is coregulated by microphthalmia transcription factor [9].
  • CLCN6 and CLCN7 belong to a novel, poorly characterized subbranch of this family [8].
  • Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters [14].
  • 3. Critical meiotic recombination events further narrowed the putative gene region to a 7.6-cM area, which contains the candidate genes ATP6L and chloride channel 7 (ClCN7) [15].
  • Similar to total TRACP, TRACP 5b appears to be a potentially useful marker to stratify individuals with ClCN7 gene mutations into clinically affected and unaffected gene carriers [16].

Analytical, diagnostic and therapeutic context of CLCN7


  1. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Kornak, U., Kasper, D., Bösl, M.R., Kaiser, E., Schweizer, M., Schulz, A., Friedrich, W., Delling, G., Jentsch, T.J. Cell (2001) [Pubmed]
  2. Polymorphisms of the CLCN7 gene are associated with BMD in women. Pettersson, U., Albagha, O.M., Mirolo, M., Taranta, A., Frattini, A., McGuigan, F.E., Vezzoni, P., Teti, A., van Hul, W., Reid, D.M., Villa, A., Ralston, S.H. J. Bone Miner. Res. (2005) [Pubmed]
  3. Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II. Kornak, U., Ostertag, A., Branger, S., Benichou, O., de Vernejoul, M.C. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  4. Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Scheel, O., Zdebik, A.A., Lourdel, S., Jentsch, T.J. Nature (2005) [Pubmed]
  5. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. Waguespack, S.G., Hui, S.L., Dimeglio, L.A., Econs, M.J. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  6. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. Kasper, D., Planells-Cases, R., Fuhrmann, J.C., Scheel, O., Zeitz, O., Ruether, K., Schmitt, A., Poët, M., Steinfeld, R., Schweizer, M., Kornak, U., Jentsch, T.J. EMBO J. (2005) [Pubmed]
  7. Recent advances in osteoclast biology and pathological bone resorption. Blair, H.C., Athanasou, N.A. Histol. Histopathol. (2004) [Pubmed]
  8. Complete genomic structure of the CLCN6 and CLCN7 putative chloride channel genes(1). Kornak, U., Bösl, M.R., Kubisch, C. Biochim. Biophys. Acta (1999) [Pubmed]
  9. The expression of clcn7 and ostm1 in osteoclasts is coregulated by microphthalmia transcription factor. Meadows, N.A., Sharma, S.M., Faulkner, G.J., Ostrowski, M.C., Hume, D.A., Cassady, A.I. J. Biol. Chem. (2007) [Pubmed]
  10. Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis. Ramírez, A., Faupel, J., Goebel, I., Stiller, A., Beyer, S., Stöckle, C., Hasan, C., Bode, U., Kornak, U., Kubisch, C. Hum. Mutat. (2004) [Pubmed]
  11. ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family. Brandt, S., Jentsch, T.J. FEBS Lett. (1995) [Pubmed]
  12. The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation. Schaller, S., Henriksen, K., Sveigaard, C., Heegaard, A.M., Hélix, N., Stahlhut, M., Ovejero, M.C., Johansen, J.V., Solberg, H., Andersen, T.L., Hougaard, D., Berryman, M., Shiødt, C.B., Sørensen, B.H., Lichtenberg, J., Christophersen, P., Foged, N.T., Delaissé, J.M., Engsig, M.T., Karsdal, M.A. J. Bone Miner. Res. (2004) [Pubmed]
  13. Degradation of the organic phase of bone by osteoclasts: a secondary role for lysosomal acidification. Henriksen, K., Sørensen, M.G., Nielsen, R.H., Gram, J., Schaller, S., Dziegiel, M.H., Everts, V., Bollerslev, J., Karsdal, M.A. J. Bone Miner. Res. (2006) [Pubmed]
  14. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. Frattini, A., Pangrazio, A., Susani, L., Sobacchi, C., Mirolo, M., Abinun, M., Andolina, M., Flanagan, A., Horwitz, E.M., Mihci, E., Notarangelo, L.D., Ramenghi, U., Teti, A., Van Hove, J., Vujic, D., Young, T., Albertini, A., Orchard, P.J., Vezzoni, P., Villa, A. J. Bone Miner. Res. (2003) [Pubmed]
  15. Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II. Waguespack, S.G., Koller, D.L., White, K.E., Fishburn, T., Carn, G., Buckwalter, K.A., Johnson, M., Kocisko, M., Evans, W.E., Foroud, T., Econs, M.J. J. Bone Miner. Res. (2003) [Pubmed]
  16. Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Alatalo, S.L., Ivaska, K.K., Waguespack, S.G., Econs, M.J., Väänänen, H.K., Halleen, J.M. Clin. Chem. (2004) [Pubmed]
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