Abstract
Male infertility is a growing health problem, which affects approximately 7% of the global male population. Nonobstructive azoospermia (NOA) is one of the most severe forms of male infertility caused by genetic defects, including chromosome structural abnormalities, Y chromosome microdeletions, or single-gene alterations. However, the etiology of up to 40% of NOA cases is unidentified. By whole-exome sequencing, we detected a homozygous 5-bp-deletion variant in exon 4 of the TEX12 gene (c.196-200del, p.L66fs, NM_031275.4) in two brothers with NOA of a nonconsanguineous Vietnamese family. This deletion variant of 5 nucleotides (ATTAG) results in a premature stop codon in exon 4 and truncation of the C-terminal. Segregation analysis by Sanger sequencing confirmed that the deletion variant was inherited in an autosomal recessive pattern. The 1st and 3rd infertile sons were homozygous for the deletion, whereas the 2nd fertile son and both parents were heterozygous. The new deletion mutation identified in TEX12 gene caused loss of function of TEX12 gene. The loss of TEX12 function has already caused infertility in male mice. Therefore, we concluded that the loss of TEX12 function may cause infertility in men. To our knowledge, this is the first case reported so far indicating disruption of human TEX12, which leads to infertility in men.
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References
Hann MC, Lau PE, Tempest HG. Meiotic recombination and male infertility: from basic science to clinical reality? Asian J Androl. 2011;13(2):212–8. https://doi.org/10.1038/aja.2011.1.
Massart A, Lissens W, Tournaye H, Stouffs K. Genetic causes of spermatogenic failure. Asian J Androl. 2012;14(1):40–8. https://doi.org/10.1038/aja.2011.67.
Tamowski S, Aston KI, Carrell DT. The use of transgenic mouse models in the study of male infertility. Syst Biol Reprod Med. 2010;56(3):260–73. https://doi.org/10.3109/19396368.2010.485244.
Zhou Y, Qin D, Tang A, Zhou D, Qin J, Yan B, et al. Developmental expression pattern of a novel gene, TSG23/Tsg23, suggests a role in spermatogenesis. Mol Hum Reprod. 2009;15(4):223–30. https://doi.org/10.1093/molehr/gap015.
Krausz C, Quintana-Murci L, McElreavey K. Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Reprod. 2000;15(7):1431–4. https://doi.org/10.1093/humrep/15.7.1431.
Handel MA, Schimenti JC. Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet. 2010;11(2):124–36. https://doi.org/10.1038/nrg2723.
Zickler D, Kleckner N. Recombination, pairing, and synapsis of homologs during meiosis. Cold Spring Harb Perspect Biol. 2015;7(6); https://doi.org/10.1101/cshperspect.a016626.
Hunter N. Meiotic recombination: the essence of heredity. Cold Spring Harb Perspect Biol. 2015;7(12); https://doi.org/10.1101/cshperspect.a016618.
Judis L, Chan ER, Schwartz S, Seftel A, Hassold T. Meiosis I arrest and azoospermia in an infertile male explained by failure of formation of a component of the synaptonemal complex. Fertil Steril. 2004;81(1):205–9. https://doi.org/10.1016/j.fertnstert.2003.05.021.
Hunt PA, Hassold TJ. Sex matters in meiosis. Science. 2002;296(5576):2181–3. https://doi.org/10.1126/science.1071907.
Gomez HL, Felipe-Medina N, Sanchez-Martin M, Davies OR, Ramos I, Garcia-Tunon I, et al. C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility. Nat Commun. 2016;7:13298. https://doi.org/10.1038/ncomms13298.
Hamer G, Wang H, Bolcun-Filas E, Cooke HJ, Benavente R, Hoog C. Progression of meiotic recombination requires structural maturation of the central element of the synaptonemal complex. J Cell Sci. 2008;121(Pt 15):2445–51. https://doi.org/10.1242/jcs.033233.
Schramm S, Fraune J, Naumann R, Hernandez-Hernandez A, Hoog C, Cooke HJ, et al. A novel mouse synaptonemal complex protein is essential for loading of central element proteins, recombination, and fertility. PLoS Genet. 2011;7(5):e1002088. https://doi.org/10.1371/journal.pgen.1002088.
Dunne OM, Davies OR. A molecular model for self-assembly of the synaptonemal complex protein SYCE3. J Biol Chem. 2019;294(23):9260–75. https://doi.org/10.1074/jbc.RA119.008404.
Dunne OM, Davies OR. Molecular structure of human synaptonemal complex protein SYCE1. Chromosoma. 2019;128(3):223–36. https://doi.org/10.1007/s00412-018-00688-z.
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(7):120099. https://doi.org/10.1098/rsob.120099.
Hamer G, Gell K, Kouznetsova A, Novak I, Benavente R, Hoog C. Characterization of a novel meiosis-specific protein within the central element of the synaptonemal complex. J Cell Sci. 2006;119(Pt 19):4025–32. https://doi.org/10.1242/jcs.03182.
Geisinger A, Benavente R. Mutations in genes coding for synaptonemal complex proteins and their impact on human fertility. Cytogenet Genome Res. 2016;150(2):77–85. https://doi.org/10.1159/000453344.
Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461(7261):272–6. https://doi.org/10.1038/nature08250.
Fan S, Jiao Y, Khan R, Jiang X, Javed AR, Ali A, et al. Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans. Am J Hum Genet. 2021;108(2):324–36. https://doi.org/10.1016/j.ajhg.2021.01.010.
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We are thankful to all patients and their families for agreeing to participate in this study.
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This research is funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 108.01-2018.316.
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This study was approved by the Institutional Review Board of the Institute of Genome Research, Vietnam Academy of Science and Technology (No. 3.1-2019/HĐĐĐ-NCHG). All the participants provided written informed consent for participation.
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Bui, M.D., Luong, T.L.A., Tran, H.D. et al. A Novel Frameshift Microdeletion of the TEX12 Gene Caused Infertility in Two Brothers with Nonobstructive Azoospermia. Reprod. Sci. 30, 2876–2881 (2023). https://doi.org/10.1007/s43032-023-01226-8
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DOI: https://doi.org/10.1007/s43032-023-01226-8