Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
Authors: Fernando Benavides
Jean-Louis Guénet
Carlos J Perez
Jean Jaubert
Craig D Platt
Huan Zhang
Taiping Chen
Meng-Hua Zhou
Hui-Lin Pan
Raúl Estévez
Jianqiang Bao
Raif S Geha
Qinghua Shi
Jeesun Kim
Yue Lu
Tewfik Hamidi
Meichun Deng
Sharon Yr Dent
Mark T Bedford
Kevin Lin
Janet Chou
Caitlin J Murphy
John H Richburg
Héctor Gaitán-Peñas
Yuying Huang
Journal: JCI Insight (2018)
Discipline: CLINICAL MEDICINE
Keywords: Fertility; Genetics; Ion channels; Reproductive Biology.
Affiliations: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA., School of Life Science, University of Science and Technology of China, Hefei, China., The University of Texas at Austin, College of Pharmacy, Austin, Texas, USA., Unité de Génétique de la Souris, Institut Pasteur, Paris, France., Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA., Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Unitat de Fisiología, Departament de Ciències Fisiològiques, IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain., U-750, CIBERER, ISCIII, Barcelona, Spain., UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA.

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&gt;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. 

Retracted: No

PubPeer comments:
 Two images in Figure 5C appear to overlap. *** ![file] , 
 I will show this to Dr. Bao because he prepared this figure with his pictures. Thanks , 
 #2 Thank you for your reply and for looping in the first author. , 
 Any development in this case? , 
 Dr. Bao moved back to China and I donu2019t have news. Clearly it is the same pic, it is an unintentional mistake. We took hundreds of pictures supporting our data (confirmed also by other publications ). , 
 There also appears to be an image duplication between Figure 2F and Figure 5C (magenta boxes), although the images seem to be described and cropped differently. Perhaps the corresponding author can contact the journal to discuss remedies given the difficulties contacting the first author. One would expect the original images to still be available after only 4 years after publication. *** ![file] ,