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  The G215R Mutation in the Cl-/H+-Antiporter ClC-7 Found in ADO II Osteopetrosis Does Not Abolish Function but Causes a Severe Trafficking Defect

Schulz, P., Werner, J., Stauber, T., Henriksen, K., & Fendler, K. (2010). The G215R Mutation in the Cl-/H+-Antiporter ClC-7 Found in ADO II Osteopetrosis Does Not Abolish Function but Causes a Severe Trafficking Defect. PLoS One, 5(9): e12585. doi:10.1371/journal.pone.0012585.

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 Creators:
Schulz, Patrick1, Author           
Werner, Johannes1, Author           
Stauber, Tobias, Author
Henriksen, Kim, Author
Fendler, Klaus1, Author           
Affiliations:
1Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max Planck Society, ou_2068289              

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 Abstract: Background: ClC-7 is a ubiquitous transporter which is broadly expressed in mammalian tissues. It is implied in the pathogenesis of lysosomal storage disease and osteopetrosis. Because of its endosomal/lysosomal localization it is still poorly characterized. Methodology/Principal Findings: An electrophysiological characterization of rat ClC-7 using solid-supported membranebased electrophysiology is presented. The measured currents show the characteristics of ClC-7 and confirm its function as a Cl-/H+-antiporter. We have used rat ClC-7 in CHO cells as a model system to investigate the functionality and cellular localization of the wt transporter and its variant G213R ClC-7 which is the analogue of human G215R ClC-7 responsible for autosomal dominant osteopetrosis type II. Our study shows that rat G213R ClC-7 is functional but has a localization defect in CHO cells which prevents it from being correctly targeted to the lysosomal membrane. The electrophysiological assay is tested as a tool for drug discovery. The assay is validated with a number of drug candidates. It is shown that ClC-7 is inhibited by DIDS, NPPB and NS5818 at micromolar concentrations. Conclusions/Significance: It is suggested that the scenario found in the CHO model system also applies to the human transporter and that mislocalization rather than impaired functionality of G215R ClC-7 is the primary cause of the related autosomal dominant osteopetrosis type II. Furthermore, the robust solid-supported membrane-based electrophysiological assay is proposed for rapid screening for potential ClC-7 inhibitors which are discussed for treatment of osteoporosis.

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Language(s): eng - English
 Dates: 2010-09
 Publication Status: Published online
 Pages: 7
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 532779
DOI: 10.1371/journal.pone.0012585
 Degree: -

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Title: PLoS One
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 5 (9) Sequence Number: e12585 Start / End Page: - Identifier: ISSN: 1932-6203
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000277850