TY - JOUR
T1 - Pathogenic variations in Germ Cell Nuclear Acidic Peptidase (GCNA) are associated with human male infertility
AU - Arafat, Maram
AU - Kleiman, Sandra E.
AU - AbuMadighem, Ali
AU - Zeadna, Atif
AU - Levitas, Eliahu
AU - Vardi, Iris Har
AU - Barda, Shimi
AU - Lehavi, Ofer
AU - Hauser, Ron
AU - Lunenfeld, Eitan
AU - Huleihel, Mahmoud
AU - Gershoni, Moran
AU - Parvari, Ruti
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to European Society of Human Genetics.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85113256344&partnerID=8YFLogxK
U2 - 10.1038/s41431-021-00946-2
DO - 10.1038/s41431-021-00946-2
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C2 - 34413498
AN - SCOPUS:85113256344
SN - 1018-4813
VL - 29
SP - 1781
EP - 1788
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 12
ER -