Scrutinizing the human TEX genes in the context of human male infertility.
TEX genes
TEX10
TEX13B
TEX27
TEX33
azoospermia
genetics
male infertility
Journal
Andrology
ISSN: 2047-2927
Titre abrégé: Andrology
Pays: England
ID NLM: 101585129
Informations de publication
Date de publication:
18 Aug 2023
18 Aug 2023
Historique:
revised:
12
07
2023
received:
06
03
2023
accepted:
06
08
2023
medline:
18
8
2023
pubmed:
18
8
2023
entrez:
18
8
2023
Statut:
aheadofprint
Résumé
Infertility affects around 15% of all couples worldwide and is increasingly linked to variants in genes specifically expressed in the testis. Well-established causes of male infertility include pathogenic variants in the genes TEX11, TEX14, and TEX15, while few studies have recently reported variants in TEX13B, TEX13C, FAM9A (TEX39A), and FAM9B (TEX39B). We aimed at screening for novel potential candidate genes among the human TEX ("testis expressed") genes as well as verifying previously described disease associations in this set of genes. To this end, we screened the exome sequencing data of 1305 men, including 1056 crypto- and azoospermic individuals, and determined cell-specific expression by analyzing testis-specific single-cell RNA sequencing data for genes with identified variants. To investigate the overarching role in male fertility, we generated testis-specific knockdown (KD) models of all 10 orthologous TEX genes in Drosophila melanogaster. We detected rare potential disease-causing variants in TEX10, TEX13A, TEX13B, TEX13C, TEX13D, ZFAND3 (TEX27), TEX33, FAM9A (TEX39A), and FAM9B (TEX39B), in 28 infertile men, of which 15 men carried variants in TEX10, TEX27, and TEX33. The KD of TEX2, TEX9, TEX10, TEX13, ZFAND3 (TEX27), TEX28, TEX30, NFX1 (TEX42), TEX261, and UTP4 (TEX292) in Drosophila resulted in normal fertility. Based on our findings, the autosomal dominant predicted genes TEX10 and ZFAND3 (TEX27) and the autosomal recessive predicted gene TEX33, which all three are conceivably required for germ cell maturation, were identified as novel potential candidate genes for human non-obstructive azoospermia. We additionally identified hemizygous loss-of-function (LoF) variants in TEX13B, TEX13C, and FAM9A (TEX39A) as unlikely monogenic culprits of male infertility as LoF variants were also found in control men. Our findings concerning the X-linked genes TEX13B, TEX13C, and FAM9A (TEX39A) contradict previous reports and will decrease false-positive reports in genetic diagnostics of azoospermic men.
Sections du résumé
BACKGROUND
BACKGROUND
Infertility affects around 15% of all couples worldwide and is increasingly linked to variants in genes specifically expressed in the testis. Well-established causes of male infertility include pathogenic variants in the genes TEX11, TEX14, and TEX15, while few studies have recently reported variants in TEX13B, TEX13C, FAM9A (TEX39A), and FAM9B (TEX39B).
OBJECTIVES
OBJECTIVE
We aimed at screening for novel potential candidate genes among the human TEX ("testis expressed") genes as well as verifying previously described disease associations in this set of genes.
MATERIALS AND METHODS
METHODS
To this end, we screened the exome sequencing data of 1305 men, including 1056 crypto- and azoospermic individuals, and determined cell-specific expression by analyzing testis-specific single-cell RNA sequencing data for genes with identified variants. To investigate the overarching role in male fertility, we generated testis-specific knockdown (KD) models of all 10 orthologous TEX genes in Drosophila melanogaster.
RESULTS
RESULTS
We detected rare potential disease-causing variants in TEX10, TEX13A, TEX13B, TEX13C, TEX13D, ZFAND3 (TEX27), TEX33, FAM9A (TEX39A), and FAM9B (TEX39B), in 28 infertile men, of which 15 men carried variants in TEX10, TEX27, and TEX33. The KD of TEX2, TEX9, TEX10, TEX13, ZFAND3 (TEX27), TEX28, TEX30, NFX1 (TEX42), TEX261, and UTP4 (TEX292) in Drosophila resulted in normal fertility.
DISCUSSION
CONCLUSIONS
Based on our findings, the autosomal dominant predicted genes TEX10 and ZFAND3 (TEX27) and the autosomal recessive predicted gene TEX33, which all three are conceivably required for germ cell maturation, were identified as novel potential candidate genes for human non-obstructive azoospermia. We additionally identified hemizygous loss-of-function (LoF) variants in TEX13B, TEX13C, and FAM9A (TEX39A) as unlikely monogenic culprits of male infertility as LoF variants were also found in control men.
CONCLUSION
CONCLUSIONS
Our findings concerning the X-linked genes TEX13B, TEX13C, and FAM9A (TEX39A) contradict previous reports and will decrease false-positive reports in genetic diagnostics of azoospermic men.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.
Références
Jarow J, Sigman M, Kolettis PN, et al. AUA guideline infertility. In AUA Clinical Guidelines. 2010;1-38.
Houston BJ, Riera-Escamilla A, Wyrwoll MJ, et al. A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene−disease relationships. Hum Reprod Update. 2021;28:15-29.
Lonsdale J, Thomas J, Salvatore M, et al. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580-585.
Davies OR, Maman JD, Pellegrini L. Structural analysis of the human SYCE2-TEX12 complex provides molecular insights into synaptonemal complex assembly. Open Biol. 2012;2:120099.
Strande NT, Riggs ER, Buchanan AH, et al. Evaluating the clinical validity of gene−disease associations: an evidence-based framework developed by the clinical genome resource. Am J Hum Genet. 2017;100:895-906.
Wyrwoll MJ, Köckerling N, Vockel M, et al. Genetic architecture of azoospermia-time to advance the standard of care. Eur Urol. 2022;83:452-462.
Chen S, Wang G, Zheng X, et al. Whole-exome sequencing of a large Chinese azoospermia and severe oligospermia cohort identifies novel infertility causative variants and genes. Hum Mol Genet. 2020;29:2451-2459.
Riera-Escamilla A, Vockel M, Nagirnaja L, et al. Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure. Am J Hum Genet. 2022;109:1458-1471.
Malcher A, Stokowy T, Berman A, et al. Whole genome sequencing identifies new candidate genes for nonobstructive azoospermia. Andrology. 2022;10:1605-1624.
Lee S, Lee S-H, Chung T-G, et al. Molecular and cytogenetic characterization of two azoospermic patients with X-autosome translocation. J Assist Reprod Genet. 2003;20:385-389.
Bellil H, Ghieh F, Hermel E, Mandon-Pepin B, Vialard F. Human testis-expressed (TEX) genes: a review focused on spermatogenesis and male fertility. Basic Clin Androl. 2021;31:9.
Karlsson M, Zhang C, Méar L, et al. A single-cell type transcriptomics map of human tissues. Sci Adv. 2021;7:eabh2169.
Quinodoz M, Royer-Bertrand B, Cisarova K, Di Gioia SA, Superti-Furga A, Rivolta C. DOMINO: using machine learning to predict genes associated with dominant disorders. Am J Hum Genet. 2017;101:623-629.
Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434-443.
Collins RL, Glessner JT, Porcu E, et al. A cross-disorder dosage sensitivity map of the human genome. Cell. 2022;185:3041-3055.
Ding J, Huang X, Shao N, et al. Tex10 coordinates epigenetic control of super-enhancer activity in pluripotency and reprogramming. Cell Stem Cell. 2015;16:653-668.
Kim D, Hong SH, Han G, Cho C. Analysis of mouse male germ cell-specific or -predominant Tex13 family genes encoding proteins with transcriptional repressor activity. Mol Biol Rep. 2021;48:3017-3022.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-423.
Yu J, Wu H, Wen Y, et al. Identification of seven genes essential for male fertility through a genome-wide association study of non-obstructive azoospermia and RNA interference-mediated large-scale functional screening in Drosophila. Hum Mol Genet. 2015;24:1493-1503.
Raymond CS, Murphy MW, O'Sullivan MG, Bardwell VJ, Zarkower D. Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 2000;14:2587-2595.
Hackstein JH, Hochstenbach R, Pearson PL. Towards an understanding of the genetics of human male infertility: lessons from flies. Trends Genet. 2000;16:565-572.
Li D, Yang J, Ma F, et al. The pluripotency factor Tex10 finetunes Wnt signaling for PGC and male germline development. bioRxiv. 2023.02.23.529824. 2023.
de Luis O, López-Fernández LA, del Mazo J. Tex27, a gene containing a zinc-finger domain, is up-regulated during the haploid stages of spermatogenesis. Exp Cell Res. 1999;249:320-326.
Ma K, Liao M, Liu F, Ye B, Sun F, Yue GH. Charactering the ZFAND3 gene mapped in the sex-determining locus in hybrid tilapia (Oreochromis spp.). Sci Rep. 2016;6:25471.
Fakhro KA, Elbardisi H, Arafa M, et al. Point-of-care whole-exome sequencing of idiopathic male infertility. Genet Med. 2018;20:1365-1373.
Li Y, Wu Y, Khan I, et al. M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination. EMBO Rep. 2023;24:e55778.
Wyrwoll MJ, Temel ŞG, Nagirnaja L, 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;107:342-351.
Xia M, Xia J, Niu C, et al. Testis-expressed protein Tex33 is not essential for spermiogenesis and fertility in mice. Mol Med Rep. 2020;23:317.
Zhu Z, Zhang X, Zeng W, et al. Spermatogenesis is normal in Tex33 knockout mice. PeerJ. 2020;8:e9629.
Dicke A-K, Pilatz A, Wyrwoll MJ, et al. DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia. Commun Biol. 2023;6:350.
Matsumura T, Endo T, Isotani A, Ogawa M, Ikawa M. An azoospermic factor gene, Ddx3y and its paralog, Ddx3x are dispensable in germ cells for male fertility. J Reprod Dev. 2019;65:121-128.
Baldarelli RM, Smith CM, Finger JH, et al. The mouse Gene Expression Database (GXD): 2021 update. Nucleic Acids Res. 2021;49:D924-D931.
Bult CJ, Blake JA, Smith CL, et al. Mouse Genome Database (MGD) 2019. Nucleic Acids Res. 2019;47:D801-D806.
Martinez-Garay I, Jablonka S, Sutajova M, Steuernagel P, Gal A, Kutsche K. A new gene family (FAM9) of low-copy repeats in Xp22.3 expressed exclusively in testis: implications for recombinations in this region. Genomics. 2002;80:259-267.
Kobayashi W, Hosoya N, Machida S, Miyagawa K, Kurumizaka H. SYCP3 regulates strand invasion activities of RAD51 and DMC1. Genes Cells. 2017;22:799-809.
Zhuang X, Feng X, Tang W, et al. FAM9B serves as a novel meiosis-related protein localized in meiotic chromosome cores and is associated with human gametogenesis. PLoS One. 2021;16:e0257248.
Chung J-J, Miki K, Kim D, et al. CatSperζ regulates the structural continuity of sperm Ca2+ signaling domains and is required for normal fertility. eLife. 2017;6:e23082.
Djureinovic D, Fagerberg L, Hallström B, et al. The human testis-specific proteome defined by transcriptomics and antibody-based profiling. Mol Hum Reprod. 2014;20:476-488.
World Health Organization (WHO). WHO Laboratory Manual for Examination and Processing of Human Semen. 6th ed. 2021.
Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285.
Wyrwoll MJ, Temel ŞG, Nagirnaja L, 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;107:342-351.
Letunic I, Khedkar S, Bork P. SMART: recent updates, new developments and status in 2020. Nucleic Acids Res. 2021;49:D458-D460.
Bateman A, Martin M-J, Orchard S, et al. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res. 2021;49:D480-D489.
Waterhouse A, Bertoni M, Bienert S, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46:296-303.
Di Persio S, Tekath T, Siebert-Kuss LM, et al. Single-cell RNA-seq unravels alterations of the human spermatogonial stem cell compartment in patients with impaired spermatogenesis. Cell Rep Med. 2021;2:100395.
Hu Y, Flockhart I, Vinayagam A, et al. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinformatics. 2011;12:357.
Li H, Janssens J, de Waegeneer M, et al. Fly Cell Atlas: a single-nucleus transcriptomic atlas of the adult fruit fly. Science. 2022;375:eabk2432.
Kwon JT, Jin S, Choi H, et al. TEX13 is a novel male germ cell-specific nuclear protein potentially involved in transcriptional repression. FEBS Lett. 2016;590:3526-3537.