Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice

Bao, Jianqiang; Perez, Carlos J.; Kim, Jeesun; Zhang, Huan; Murphy, Caitlin J.; Hamidi, Tewfik; Jaubert, Jean; Platt, Craig D.; Chou, Janet; Deng, Meichun; Zhou, Meng-Hua; Huang, Yuying; Gaitán-Peñas, Héctor; Guenet, Jean-Louis; Lin, Kevin; Lu, Yue; Chen, Taiping; Bedford, Mark T.; Dent, Sharon Y. R.; Richburg, John H.; Estévez Povedano, Raúl; Pan, Hui-Lin; Geha, Raif S.; Shi, Qinghua; Benavides, Fernando G.

Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice

Ion channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. N...

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Autores:	Bao, Jianqiang, Perez, Carlos J., Kim, Jeesun, Zhang, Huan, Murphy, Caitlin J., Hamidi, Tewfik, Jaubert, Jean, Platt, Craig D., Chou, Janet, Deng, Meichun, Zhou, Meng-Hua, Huang, Yuying, Gaitán-Peñas, Héctor, Guenet, Jean-Louis, Lin, Kevin, Lu, Yue, Chen, Taiping, Bedford, Mark T., Dent, Sharon Y. R., Richburg, John H., Estévez Povedano, Raúl, Pan, Hui-Lin, Geha, Raif S., Shi, Qinghua, Benavides, Fernando G.
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2018
País:	España
Institución:	Universidad de Barcelona
Repositorio:	Dipòsit Digital de la UB
OAI Identifier:	oai:diposit.ub.edu:2445/172306
Acceso en línea:	https://hdl.handle.net/2445/172306
Access Level:	acceso abierto
Palabra clave:	Esterilitat en els animals Anions Infertility in animals

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spelling	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in miceBao, JianqiangPerez, Carlos J.Kim, JeesunZhang, HuanMurphy, Caitlin J.Hamidi, TewfikJaubert, JeanPlatt, Craig D.Chou, JanetDeng, MeichunZhou, Meng-HuaHuang, Yuying Gaitán-Peñas, HéctorGuenet, Jean-LouisLin, KevinLu, YueChen, TaipingBedford, Mark T.Dent, Sharon Y. R.Richburg, John H.Estévez Povedano, RaúlPan, Hui-LinGeha, Raif S.Shi, QinghuaBenavides, Fernando G.Esterilitat en els animalsAnionsInfertility in animalsAnionsIon channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. Nevertheless, the contribution of LRRC8A and its dependent VRAC activity in the germ cell lineage remain unknown. By utilizing a spontaneous Lrrc8a mouse mutation (c.1325delTG, p.F443*) and genetically engineered mouse models, we demonstrate that LRRC8A-dependent VRAC activity is essential for male germ cell development and fertility. Lrrc8a-null male germ cells undergo progressive degeneration independent of the apoptotic pathway during postnatal testicular development. Lrrc8a-deficient mouse sperm exhibit multiple morphological abnormalities of the flagella (MMAF), a feature commonly observed in the sperm of infertile human patients. Importantly, we identified a human patient with a rare LRRC8A hypomorphic mutation (c.1634G>A, p.Arg545His) possibly linked to Sertoli cell-only syndrome (SCOS), a male sterility disorder characterized by the loss of germ cells. Thus, LRRC8A is a critical factor required for germ cell development and volume regulation in the mouse, and it might serve as a novel diagnostic and therapeutic target for SCOS patients.American Society for Clinical Investigation2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/172306Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1172/jci.insight.99767JCI Insight, 2018, vol. 3, num. 16, p. e99767https://doi.org/10.1172/jci.insight.99767(c) American Society for Clinical Investigation, 2018info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1723062026-05-27T06:46:51Z
dc.title.none.fl_str_mv	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
title	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
spellingShingle	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice Bao, Jianqiang Esterilitat en els animals Anions Infertility in animals Anions
title_short	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
title_full	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
title_fullStr	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
title_full_unstemmed	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
title_sort	Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
dc.creator.none.fl_str_mv	Bao, Jianqiang Perez, Carlos J. Kim, Jeesun Zhang, Huan Murphy, Caitlin J. Hamidi, Tewfik Jaubert, Jean Platt, Craig D. Chou, Janet Deng, Meichun Zhou, Meng-Hua Huang, Yuying Gaitán-Peñas, Héctor Guenet, Jean-Louis Lin, Kevin Lu, Yue Chen, Taiping Bedford, Mark T. Dent, Sharon Y. R. Richburg, John H. Estévez Povedano, Raúl Pan, Hui-Lin Geha, Raif S. Shi, Qinghua Benavides, Fernando G.
author	Bao, Jianqiang
author_facet	Bao, Jianqiang Perez, Carlos J. Kim, Jeesun Zhang, Huan Murphy, Caitlin J. Hamidi, Tewfik Jaubert, Jean Platt, Craig D. Chou, Janet Deng, Meichun Zhou, Meng-Hua Huang, Yuying Gaitán-Peñas, Héctor Guenet, Jean-Louis Lin, Kevin Lu, Yue Chen, Taiping Bedford, Mark T. Dent, Sharon Y. R. Richburg, John H. Estévez Povedano, Raúl Pan, Hui-Lin Geha, Raif S. Shi, Qinghua Benavides, Fernando G.
author_role	author
author2	Perez, Carlos J. Kim, Jeesun Zhang, Huan Murphy, Caitlin J. Hamidi, Tewfik Jaubert, Jean Platt, Craig D. Chou, Janet Deng, Meichun Zhou, Meng-Hua Huang, Yuying Gaitán-Peñas, Héctor Guenet, Jean-Louis Lin, Kevin Lu, Yue Chen, Taiping Bedford, Mark T. Dent, Sharon Y. R. Richburg, John H. Estévez Povedano, Raúl Pan, Hui-Lin Geha, Raif S. Shi, Qinghua Benavides, Fernando G.
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Esterilitat en els animals Anions Infertility in animals Anions
topic	Esterilitat en els animals Anions Infertility in animals Anions
description	Ion channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. Nevertheless, the contribution of LRRC8A and its dependent VRAC activity in the germ cell lineage remain unknown. By utilizing a spontaneous Lrrc8a mouse mutation (c.1325delTG, p.F443*) and genetically engineered mouse models, we demonstrate that LRRC8A-dependent VRAC activity is essential for male germ cell development and fertility. Lrrc8a-null male germ cells undergo progressive degeneration independent of the apoptotic pathway during postnatal testicular development. Lrrc8a-deficient mouse sperm exhibit multiple morphological abnormalities of the flagella (MMAF), a feature commonly observed in the sperm of infertile human patients. Importantly, we identified a human patient with a rare LRRC8A hypomorphic mutation (c.1634G>A, p.Arg545His) possibly linked to Sertoli cell-only syndrome (SCOS), a male sterility disorder characterized by the loss of germ cells. Thus, LRRC8A is a critical factor required for germ cell development and volume regulation in the mouse, and it might serve as a novel diagnostic and therapeutic target for SCOS patients.
publishDate	2018
dc.date.none.fl_str_mv	2018
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/172306
url	https://hdl.handle.net/2445/172306
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.99767 JCI Insight, 2018, vol. 3, num. 16, p. e99767 https://doi.org/10.1172/jci.insight.99767
dc.rights.none.fl_str_mv	(c) American Society for Clinical Investigation, 2018 info:eu-repo/semantics/openAccess
rights_invalid_str_mv	(c) American Society for Clinical Investigation, 2018
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	American Society for Clinical Investigation
publisher.none.fl_str_mv	American Society for Clinical Investigation
dc.source.none.fl_str_mv	Articles publicats en revistes (Ciències Fisiològiques) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona
instname_str	Universidad de Barcelona
reponame_str	Dipòsit Digital de la UB
collection	Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15.300719

Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice

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