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.

<h4>Background</h4>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.<h4>Methodology/p...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Patrick Schulz, Johannes Werner, Tobias Stauber, Kim Henriksen, Klaus Fendler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e46a718215eb4955be96d388cc537ab9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e46a718215eb4955be96d388cc537ab9
record_format	dspace
spelling	oai:doaj.org-article:e46a718215eb4955be96d388cc537ab92021-11-18T06:35:25ZThe G215R mutation in the Cl-/H+-antiporter ClC-7 found in ADO II osteopetrosis does not abolish function but causes a severe trafficking defect.1932-620310.1371/journal.pone.0012585https://doaj.org/article/e46a718215eb4955be96d388cc537ab92010-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20830208/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>An electrophysiological characterization of rat ClC-7 using solid-supported membrane-based 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.<h4>Conclusions/significance</h4>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.Patrick SchulzJohannes WernerTobias StauberKim HenriksenKlaus FendlerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 9, p e12585 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Patrick Schulz Johannes Werner Tobias Stauber Kim Henriksen Klaus Fendler 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.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>An electrophysiological characterization of rat ClC-7 using solid-supported membrane-based 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.<h4>Conclusions/significance</h4>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.
format	article
author	Patrick Schulz Johannes Werner Tobias Stauber Kim Henriksen Klaus Fendler
author_facet	Patrick Schulz Johannes Werner Tobias Stauber Kim Henriksen Klaus Fendler
author_sort	Patrick Schulz
title	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.
title_short	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.
title_full	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.
title_fullStr	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.
title_full_unstemmed	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.
title_sort	g215r mutation in the cl-/h+-antiporter clc-7 found in ado ii osteopetrosis does not abolish function but causes a severe trafficking defect.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/e46a718215eb4955be96d388cc537ab9
work_keys_str_mv	AT patrickschulz theg215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT johanneswerner theg215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT tobiasstauber theg215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT kimhenriksen theg215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT klausfendler theg215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT patrickschulz g215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT johanneswerner g215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT tobiasstauber g215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT kimhenriksen g215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect AT klausfendler g215rmutationintheclhantiporterclc7foundinadoiiosteopetrosisdoesnotabolishfunctionbutcausesaseveretraffickingdefect
_version_	1718424451318546432

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.

Ejemplares similares