Pathogenic variations in Germ Cell Nuclear Acidic Peptidase (GCNA) are associated with human male infertility.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
21
04
2021
accepted:
09
08
2021
revised:
29
06
2021
pubmed:
21
8
2021
medline:
23
3
2022
entrez:
20
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34413498
doi: 10.1038/s41431-021-00946-2
pii: 10.1038/s41431-021-00946-2
pmc: PMC8632907
doi:
Substances chimiques
GCNA protein, human
0
Nuclear Proteins
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1781-1788Informations de copyright
© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.
Références
Krausz C, Riera-Escamilla A. Genetics of male infertility. Nat Rev Urol. 2018;15:369–84.
pubmed: 29622783
doi: 10.1038/s41585-018-0003-3
Tüttelmann F, Ruckert C, Röpke A. Disorders of spermatogenesis: perspectives for novel genetic diagnostics after 20 years of unchanged routine. Medizinische Genetik: Mitteilungsblatt des Berufsverbandes Medizinische Genetik eV. 2018;30:12–20.
doi: 10.1007/s11825-018-0181-7
Agarwal A, Baskaran S, Parekh N, Cho CL, Henkel R, Vij S, et al. Male infertility. Lancet. 2021;397:319–33.
pubmed: 33308486
doi: 10.1016/S0140-6736(20)32667-2
Jarvi K, Lo K, Fischer A, Grantmyre J, Zini A, Chow V, et al. CUA guideline: the workup of azoospermic males. Can Urological Assoc J = J de l’Assoc des urologues du Can. 2010;4:163–7.
doi: 10.5489/cuaj.10050
Schilit SLP, Menon S, Friedrich C, Kammin T, Wilch E, Hanscom C, et al. SYCP2 translocation-mediated dysregulation and frameshift variants cause human male infertility. Am J Hum Genet. 2020;106:41–57.
pubmed: 31866047
doi: 10.1016/j.ajhg.2019.11.013
Cooke HJ, Saunders PT. Mouse models of male infertility. Nat Rev Genet. 2002;3:790–801.
pubmed: 12360237
doi: 10.1038/nrg911
Schultz N, Hamra FK, Garbers DL. A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets. Proc Natl Acad Sci USA. 2003;100:12201–6.
pubmed: 14526100
pmcid: 218736
doi: 10.1073/pnas.1635054100
Singh P, Schimenti JC. The genetics of human infertility by functional interrogation of SNPs in mice. Proc Natl Acad Sci USA. 2015;112:10431–6.
pubmed: 26240362
pmcid: 4547237
doi: 10.1073/pnas.1506974112
Oud MS, Volozonoka L, Smits RM, Vissers L, Ramos L, Veltman JA. A systematic review and standardized clinical validity assessment of male infertility genes. Hum Reprod. 2019;34:932–41.
pubmed: 30865283
pmcid: 6505449
doi: 10.1093/humrep/dez022
van Wolfswinkel JC. Piwi and potency: PIWI proteins in animal stem cells and regeneration. Integr Comp Biol. 2014;54:700–13.
pubmed: 24948137
doi: 10.1093/icb/icu084
Wyrwoll MJ, Temel ŞG, Nagirnaja L, Oud MS, Lopes AM, van der Heijden GW, et al. Bi-allelic mutations in M1AP are a frequent cause of meiotic arrest and severely impaired spermatogenesis leading to male infertility. Am J Hum Genet. 2020;107:342–51.
pubmed: 32673564
pmcid: 7413853
doi: 10.1016/j.ajhg.2020.06.010
Kasak L, Punab M, Nagirnaja L, Grigorova M, Minajeva A, Lopes AM, et al. Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive Azoospermia. Am J Hum Genet. 2018;103:200–12.
pubmed: 30075111
pmcid: 6080835
doi: 10.1016/j.ajhg.2018.07.005
Miyamoto T, Hasuike S, Yogev L, Maduro MR, Ishikawa M, Westphal H, et al. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet. 2003;362:1714–9.
pubmed: 14643120
doi: 10.1016/S0140-6736(03)14845-3
Maor-Sagie E, Cinnamon Y, Yaacov B, Shaag A, Goldsmidt H, Zenvirt S, et al. Deleterious mutation in SYCE1 is associated with non-obstructive azoospermia. J Assist Reprod Genet. 2015;32:887–91.
pubmed: 25899990
pmcid: 4491075
doi: 10.1007/s10815-015-0445-y
Yatsenko AN, Georgiadis AP, Röpke A, Berman AJ, Jaffe T, Olszewska M, et al. X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med. 2015;372:2097–107.
pubmed: 25970010
pmcid: 4470617
doi: 10.1056/NEJMoa1406192
Gershoni M, Hauser R, Yogev L, Lehavi O, Azem F, Yavetz H, et al. A familial study of azoospermic men identifies three novel causative mutations in three new human Azoospermia genes. Genet Med. 2017;19:998–1006.
pubmed: 28206990
doi: 10.1038/gim.2016.225
Gershoni M, Hauser R, Barda S, Lehavi O, Arama E, Pietrokovski S, et al. A new MEIOB mutation is a recurrent cause for azoospermia and testicular meiotic arrest. Hum Reprod. 2019;34:666–71.
pubmed: 30838384
doi: 10.1093/humrep/dez016
Arafat M, Har-Vardi I, Harlev A, Levitas E, Zeadna A, Abofoul-Azab M, et al. Mutation in TDRD9 causes non-obstructive azoospermia in infertile men. J Med Genet. 2017;54:633–9.
pubmed: 28536242
doi: 10.1136/jmedgenet-2017-104514
Carmell MA, Dokshin GA, Skaletsky H, Hu YC, van Wolfswinkel JC, Igarashi KJ, et al. A widely employed germ cell marker is an ancient disordered protein with reproductive functions in diverse eukaryotes. Elife 2016;5:e19993.
pubmed: 27718356
pmcid: 5098910
doi: 10.7554/eLife.19993
Yudkina AV, Dvornikova AP, Zharkov DO. Variable termination sites of DNA polymerases encountering a. DNA-protein cross-link. 2018;13:e0198480.
Enders GC, May JJ 2nd. Developmentally regulated expression of a mouse germ cell nuclear antigen examined from embryonic day 11 to adult in male and female mice. Developmental Biol. 1994;163:331–40.
doi: 10.1006/dbio.1994.1152
Bhargava V, Goldstein CD, Russell L, Xu L, Ahmed M, Li W, et al. GCNA preserves genome integrity and fertility across species. Dev Cell. 2020;52:38–52.e10.
pubmed: 31839537
doi: 10.1016/j.devcel.2019.11.007
Dokshin GA, Davis GM, Sawle AD, Eldridge MD, Nicholls PK, Gourley TE, et al. GCNA interacts with Spartan and Topoisomerase II to regulate genome stability. Dev Cell. 2020;52:53–68.e6.
pubmed: 31839538
doi: 10.1016/j.devcel.2019.11.006
Björndahl L, Barratt CL, Mortimer D, Jouannet P. ‘How to count sperm properly’: checklist for acceptability of studies based on human semen analysis. Hum Reprod. 2016;31:227–32.
pubmed: 26682580
Hauser R, Botchan A, Amit A, Ben Yosef D, Gamzu R, Paz G, et al. Multiple testicular sampling in non-obstructive azoospermia-is it necessary? Hum Reprod. 1998;13:3081–5.
pubmed: 9853860
doi: 10.1093/humrep/13.11.3081
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinforma (Oxf, Engl). 2014;30:2114–20.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinforma (Oxf, Engl). 2009;25:1754–60.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.
pubmed: 20644199
pmcid: 2928508
doi: 10.1101/gr.107524.110
Arafat M, Harlev A, Har-Vardi I, Levitas E, Priel T, Gershoni M, et al. Mutation in CATIP (C2orf62) causes oligoteratoasthenozoospermia by affecting actin dynamics. J Med Genet. 2020. https://doi.org/10.1136/jmedgenet-2019-106825 .
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.
pubmed: 20601685
pmcid: 2938201
doi: 10.1093/nar/gkq603
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–9.
pubmed: 10802651
pmcid: 3037419
doi: 10.1038/75556
Eppig JT, Blake JA, Bult CJ, Kadin JA, Richardson JE. The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease. Nucleic Acids Res. 2015;43:D726–36.
pubmed: 25348401
doi: 10.1093/nar/gku967
Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60.
doi: 10.1126/science.1262110
Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinforma. 2016;54:1.30.1–1.3.
doi: 10.1002/cpbi.5
Karczewski KJ, Francioli LC. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.
Piotrkowski B, Monzón CM, Pagotto RM, Reche CG, Besio M, Cymeryng CB, et al. Effects of heme oxygenase isozymes on Leydig cells steroidogenesis. J Endocrinol. 2009;203:155–65.
pubmed: 19648213
doi: 10.1677/JOE-09-0061
Nishimura T, Nagamori I, Nakatani T, Izumi N, Tomari Y, Kuramochi-Miyagawa S. PNLDC1, mouse pre-piRNA Trimmer, is required for meiotic and post-meiotic male germ cell development. EMBO Rep. 2018;19:e44957. https://doi.org/10.15252/embr.201744957 .
Di Persio S, Saracino R, Fera S, Muciaccia B, Esposito V, Boitani C. Spermatogonial kinetics in humans. Development. 2017;144:3430–9.
Okada S, Kuroki K, Ruiz CA, Tosi AJ, Imamura M Molecular histology of spermatogenesis in the Japanese macaque monkey (Macaca fuscata). Primates. 2021;62:113–21.
pubmed: 32803510
doi: 10.1007/s10329-020-00857-8
Okada S, Kuroki K, Ruiz CA, Tosi AJ, Imamura M. Molecular histology of spermatogenesis in the Japanese macaque monkey (Macaca fuscata). Primates. 2021;62:113–21.
pubmed: 32803510
doi: 10.1007/s10329-020-00857-8
Yatsenko AN, Roy A, Chen R, Ma L, Murthy LJ, Yan W, et al. Non-invasive genetic diagnosis of male infertility using spermatozoal RNA: KLHL10 mutations in oligozoospermic patients impair homodimerization. Hum Mol Genet. 2006;15:3411–9.
pubmed: 17047026
doi: 10.1093/hmg/ddl417
Ayhan Ö, Balkan M, Guven A, Hazan R, Atar M, Tok A, et al. Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia. J Med Genet. 2014;51:239–44.
pubmed: 24431330
doi: 10.1136/jmedgenet-2013-102102
Hardy JJ, Wyrwoll MJ, McFadden W, Malcher A, Rotte N, Pollock NC, et al. Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure. Hum Genet. 2021;140:1169–82.
pubmed: 33963445
pmcid: 8266742
doi: 10.1007/s00439-021-02287-y
Stingele J, Bellelli R, Alte F, Hewitt G, Sarek G, Maslen SL, et al. Mechanism and regulation of DNA-protein crosslink repair by the DNA-dependent metalloprotease SPRTN. Mol Cell. 2016;64:688–703.
pubmed: 27871365
pmcid: 5128726
doi: 10.1016/j.molcel.2016.09.031
Parhad SS, Tu S, Weng Z, Theurkauf WE. Adaptive evolution leads to cross-species incompatibility in the piRNA transposon silencing machinery. Developmental Cell. 2017;43:60–70.e5.
pubmed: 28919205
pmcid: 5653967
doi: 10.1016/j.devcel.2017.08.012
Borgermann N, Ackermann L, Schwertman P, Hendriks IA, Thijssen K, Liu JC, et al. SUMOylation promotes protective responses to DNA-protein crosslinks. EMBO J. 2019;38:e101496.
pubmed: 30914427
pmcid: 6463212
doi: 10.15252/embj.2019101496