Pathogenic variations in Germ Cell Nuclear Acidic Peptidase (GCNA) are associated with human male infertility.

Infertility affects one in six couples, half of which are caused by a male factor. Male infertility can be caused by both, qualitative and quantitative defects, leading to Oligo- astheno-terato-zoospermia (OAT; impairment in ejaculate sperm cell concentration, motility and morphology). Azoospermia defined as complete absence of sperm cells in the ejaculation. While hundreds of genes are involved in spermatogenesis the genetic etiology of men's infertility remains incomplete.We identified a hemizygous stop gain pathogenic variation (PV) in the X-linked Germ Cell Nuclear Acidic Peptidase (GCNA), in an Azoospermic patient by exome sequencing. Assessment of the prevalence of pathogenic variations in this gene in infertile males by exome sequence data of 11 additional unrelated patients identified a probable hemizygous causative missense PV in GCNA in a severe OAT patient. Expression of GCNA in the patients' testes biopsies and the stage of spermatogonial developmental arrest were determined by immunofluorescence and immunohistochemistry. The Azoospermic patient presented spermatogenic maturation arrest with an almost complete absence of early and late primary spermatocytes and thus the complete absence of sperm. GCNA is critical for genome integrity and its loss results in genomic instability and infertility in Drosophila, C. elegans, zebrafish, and mouse. PVs in GCNA appear to be incompatible with male fertility in humans as well: A stop-gain PV caused Azoospermia and a missense PV caused severe OAT with very low fertilization rates and no pregnancy in numerous IVF treatments.

European journal of human genetics : EJHG. 2021 Aug 20 [Epub ahead of print]

Maram Arafat, Sandra E Kleiman, Ali AbuMadighem, Atif Zeadna, Eliahu Levitas, Iris Har Vardi, Shimi Barda, Ofer Lehavi, Ron Hauser, Eitan Lunenfeld, Mahmoud Huleihel, Moran Gershoni, Ruti Parvari

The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel., Institute for the Study of Fertility, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel., Department of Ruminant Science, Institute of Animal Sciences, Agricultural Research Organization, The Volcani Center, Rishon LeZion, Israel., The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. .