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Title: Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
Author: 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.
Keywords: Esterilitat en els animals
Infertility in animals
Issue Date: 23-Aug-2018
Publisher: American Society for Clinical Investigation
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: JCI Insight, 2018, vol. 3, num. 16, p. e99767
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ISSN: 2379-3708
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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