Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure

Jimmaline J Hardy; Margot J Wyrwoll; William Mcfadden; Agnieszka Malcher; Nadja Rotte; Nijole C Pollock; Sarah Munyoki; Maria V Veroli; Brendan J Houston; Miguel J Xavier; Laura Kasak; Margus Punab; Maris Laan; Sabine Kliesch; Peter Schlegel; Thomas Jaffe; Kathleen Hwang; Josip Vukina; Miguel A Brieno-Enriquez; Kyle Orwig; Judith Yanowitz; Michael Buszczak; Joris A Veltman; Manon Oud; Liina Nagirnaja; Marta Olszewska; Moira K O'Bryan; Donald F Conrad; Maciej Kurpisz; Frank Tuettelmann; Alexander N Yatsenko

Journal article

Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure

Jimmaline J Hardy, Margot J Wyrwoll, William Mcfadden, Agnieszka Malcher, Nadja Rotte, Nijole C Pollock, Sarah Munyoki, Maria V Veroli, Brendan J Houston, Miguel J Xavier, Laura Kasak, Margus Punab, Maris Laan, Sabine Kliesch, Peter Schlegel, Thomas Jaffe, Kathleen Hwang, Josip Vukina, Miguel A Brieno-Enriquez, Kyle Orwig Show all

HUMAN GENETICS | SPRINGER | Published : 2021

DOI: 10.1007/s00439-021-02287-y

Abstract

Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n = 176) did not reveal known gene-candidates but identified a potentially significant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n = 2049), 7 likely clinically relevant GCNA variants were identified. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-..

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University of Melbourne Researchers

Moira O'Bryan Author Science

Brendan Houston Author Biosciences

Grants

Awarded by Eunice Kennedy Shriver NICHD

Awarded by PA DoH

Awarded by NIH

Awarded by German Research Foundation Clinical Research Unit 'Male Germ Cells' grant DFG

Awarded by National Science Centre in Poland

Awarded by NCN

Awarded by NICHD

Awarded by National Health and Medical Research Council

Awarded by Estonian Research Council

Awarded by Netherlands Organization for Scientific Research

Awarded by Wellcome Trust

Funding Acknowledgements

This study was supported by The Eunice Kennedy Shriver NICHD Grant HD080755 (ANY), the Magee-Womens Research Institute University of Pittsburgh Start Up Fund (ANY), PA DoH Grant SAP4100085736 (ANY), NIH P50 Specialized Center Grant HD096723 (KO, ANY, DC, PNS, KH, and MBE), German Research Foundation Clinical Research Unit 'Male Germ Cells' grant DFG CRU326 (FT), National Science Centre in Poland, grants no.: 2017/26/D/NZ5/00789 (AM) and 2015/17/B/NZ2/01157; NCN 2020/37/B/NZ5/00549 (MK), Magee-Womens Research Institute University of Pittsburgh, Faculty Fellowship Award and NICHD T32 HD087194 (JH), GM125812 (MB), GM127569 (MB, JLY, and ANY), NIH R00H090289 (MABE), National Health and Medical Research Council Project grant APP1120356 (MKOB, JAV, and DC), UUKi Rutherford Fund Fellowship (BJH), Estonian Research Council, grants IUT34-12 and PRG1021 (ML), and The Netherlands Organization for Scientific Research grant no.: 918-15-667 as well as an Investigator Award in Science from the Wellcome Trust grant no.: 209451 (JAV). Computational analysis was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided.