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

Jianqiang Bao (1) , Carlos Perez (1) , Jeesun Kim (1) , Huan Zhang (2) , Caitlin Murphy (3) , Tewfik Hamidi (1) , Jean Jaubert (4) , Craig Platt (5) , Janet Chou (5) , Meichun Deng (6) , Meng-Hua Zhou (6) , Yuying Huang (6) , Héctor Gaitán-Peñas (7, 8) , Jean-Louis Guénet (4) , Kevin Lin (1) , Yue Lu (1) , Taiping Chen (9, 1) , Mark Bedford (1, 9) , Sharon Y.R. Dent (1, 9) , John Richburg (3) , Raúl Estévez (7, 8) , Hui-Lin Pan (6) , Raif Geha (10) , Qinghua Shi (2) , Fernando Benavides (9, 1)

1 The University of Texas M.D. Anderson Cancer Center [Houston]
2 School of Life Science [Heifei]
3 University of Texas at Austin [Austin]
4 Génétique de la souris - Mouse Genetics
5 Boston Children's Hospital
6 Center for Neuroscience & Pain Research [Houston]
7 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge = Bellvitge Biomedical Research Institute
8 CIBER de Enfermedades Raras (CIBERER)
9 Graduate School of Biomedical Sciences [Houston]
10 Boston Children's Hospital

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.

Mots clés: Fertility; Genetics; Ion channels; Reproductive Biology

Domaines: Génétique animale

Jianqiang Bao, Carlos Perez, Jeesun Kim, Huan Zhang, Caitlin Murphy, et al.. Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice. JCI Insight, 2018, 3 (16), pp.e99767. ⟨10.1172/jci.insight.99767⟩. ⟨pasteur-02868953⟩