Abstract
One of the most severe forms of infertility in humans, caused by gametogenic failure, is non-obstructive azoospermia (NOA). Approximately, 20–30% of men with NOA may have single-gene mutations or other genetic variables that cause this disease. While a range of single-gene mutations associated with infertility has been identified in prior whole-exome sequencing (WES) studies, current insight into the precise genetic etiology of impaired human gametogenesis remains limited. In this paper, we described a proband with NOA who experienced hereditary infertility. WES analyses identified a homozygous variant in the SUN1 (Sad1 and UNC84 domain containing 1) gene [c. 663C > A: p.Tyr221X] that segregated with infertility. SUN1 encodes a LINC complex component essential for telomeric attachment and chromosomal movement. Spermatocytes with the observed mutations were incapable of repairing double-strand DNA breaks or undergoing meiosis. This loss of SUN1 functionality contributes to significant reductions in KASH5 levels within impaired chromosomal telomere attachment to the inner nuclear membrane. Overall, our results identify a potential genetic driver of NOA pathogenesis and provide fresh insight into the role of the SUN1 protein as a regulator of prophase I progression in the context of human meiosis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
References
Anderson J, Farr S, Jamieson D, Warner L, Macaluso MJF (2009) Infertility services reported by men in the United States: National Survey Data. Fertil Steril 91:2466–2470. https://doi.org/10.1016/j.fertnstert.2008.03.022
Arshad M, Majzoub A, Esteves SJ (2020) Predictors of surgical sperm retrieval in non-obstructive azoospermia: summary of current literature. Int Urol Nephrol 52:2015–2038. https://doi.org/10.1007/s11255-020-02529-4
Bellani MA, Romanienko PJ, Cairatti DA, Camerini-Otero RD (2005) SPO11 is required for sex-body formation, and Spo11 heterozygosity rescues the prophase arrest of Atm−/− spermatocytes. J Cell Sci 118:3233–3245. https://doi.org/10.1242/jcs.02466
Bolcun-Filas E, Handel MA (2018) Meiosis: the chromosomal foundation of reproduction. Biol Reprod 99:112–126. https://doi.org/10.1093/biolre/ioy021
Bupp JM, Martin AE, Stensrud ES, Jaspersen SL (2007) Telomere anchoring at the nuclear periphery requires the budding yeast Sad1-UNC-84 domain protein Mps3. J Cell Biol 179:845–854. https://doi.org/10.1083/jcb.200706040
Burke B (2018) LINC complexes as regulators of meiosis. Curr Opin Cell Biol 52:22–29. https://doi.org/10.1016/j.ceb.2018.01.005
Chang YF, Imam JS, Wilkinson MF (2007) The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76:51–74. https://doi.org/10.1146/annurev.biochem.76.050106.093909
Chen Y, Wang Y, Chen J, Zuo W, Fan Y, Huang S, Liu Y, Chen G, Li Q, Li J, Wu J, Bian Q, Huang C, Lei M (2021) The SUN1-SPDYA interaction plays an essential role in meiosis prophase I. Nat Commun 12:3176. https://doi.org/10.1038/s41467-021-23550-w
Ding X, Xu R, Yu J, Xu T, Zhuang Y, Han M (2007) SUN1 is required for telomere attachment to nuclear envelope and gametogenesis in mice. Dev Cell 12:863–872. https://doi.org/10.1016/j.devcel.2007.03.018
Fakhro KA, Elbardisi H, Arafa M, Robay A, Rodriguez-Flores JL, Al-Shakaki A, Syed N, Mezey JG, Abi Khalil C, Malek JA, Al-Ansari A, Al Said S, Crystal RG (2018) Point-of-care whole-exome sequencing of idiopathic male infertility. Genet Med 20:1365–1373. https://doi.org/10.1038/gim.2018.10
Gershoni M, Hauser R, Barda S, Lehavi O, Arama E, Pietrokovski S, Kleiman SJ (2019) A new MEIOB mutation is a recurrent cause for azoospermia and testicular meiotic arrest. Hum Reprod 34:666–671. https://doi.org/10.1093/humrep/dez016
Gong C, Abbas T, Muhammad Z, Zhou J, Khan R, Ma H, Zhang H, Shi Q, Shi B (2022) A homozygous loss-of-function mutation in MSH5 abolishes MutSγ axial loading and causes meiotic arrest in NOA-affected individuals. Int J Mol Sci. https://doi.org/10.3390/ijms23126522
Harper L, Golubovskaya I, Cande WZ (2004) A bouquet of chromosomes. J Cell Sci 117:4025–4032. https://doi.org/10.1242/jcs.01363
Hiraoka Y, Dernburg AF (2009) The SUN rises on meiotic chromosome dynamics. Dev Cell 17:598–605. https://doi.org/10.1016/j.devcel.2009.10.014
Horn HF, Kim DI, Wright GD, Wong ES, Stewart CL, Burke B, Roux KJ (2013) A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton. J Cell Biol 202:1023–1039. https://doi.org/10.1083/jcb.201304004
Jarvi K, Lo K, Fischer A, Grantmyre J, Zini A, Chow V, Mak VJ (2010) CUA guideline: the workup of azoospermic males. Can Urol Assoc J 4:163–167. https://doi.org/10.5489/cuaj.10050
Kmonickova V, Frolikova M, Steger K, Komrskova K (2020) The role of the LINC complex in sperm development and function. Int J Mol Sci. https://doi.org/10.3390/ijms21239058
Krausz C, Riera-Escamilla A (2018) Genetics of male infertility. Nat Rev Urol 15:369–384. https://doi.org/10.1038/s41585-018-0003-3
Lee YL, Burke B (2018) LINC complexes and nuclear positioning. Semin Cell Dev Biol 82:67–76. https://doi.org/10.1016/j.semcdb.2017.11.008
Link J, Jahn D, Alsheimer M (2015) Structural and functional adaptations of the mammalian nuclear envelope to meet the meiotic requirements. Nucleus 6:93–101. https://doi.org/10.1080/19491034.2015.1004941
Long J, Huang C, Chen Y, Zhang Y, Shi S, Wu L, Liu Y, Liu C, Wu J, Lei M (2017) Telomeric TERB1-TRF1 interaction is crucial for male meiosis. Nat Struct Mol Biol 24:1073–1080. https://doi.org/10.1038/nsmb.3496
Majzoub A, Arafa M, Clemens H, Imperial J, Leisegang K, Khalafalla K, Agarwal A, Henkel R, Elbardisi H (2022) A systemic review and meta-analysis exploring the predictors of sperm retrieval in patients with non-obstructive azoospermia and chromosomal abnormalities. Andrologia 54:e14303. https://doi.org/10.1111/and.14303
Mikolcevic P, Isoda M, Shibuya H, del Barco BI, Igea A, Suja JA, Shackleton S, Watanabe Y, Nebreda AR (2016) Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope. Nat Commun 7:11084. https://doi.org/10.1038/ncomms11084
Morimoto A, Shibuya H, Zhu X, Kim J, Ishiguro K, Han M, Watanabe Y (2012) A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis. J Cell Biol 198:165–172. https://doi.org/10.1083/jcb.201204085
Mühlemann O (2016) Spermatogenesis studies reveal a distinct nonsense-mediated mRNA decay (NMD) mechanism for mRNAs with long 3’UTRs. PLoS Genet 12:e1005979. https://doi.org/10.1371/journal.pgen.1005979
Parvanov ED, Petkov PM, Paigen K (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327:835. https://doi.org/10.1126/science.1181495
Peters A, Plug A, van Vugt M, de Boer PJC (1997) A drying-down technique for the spreading of mammalian meiocytes from the male and female germline. Chromosome Res 5:66–68. https://doi.org/10.1023/a:1018445520117
Salas-Huetos A, Tüttelmann F, Wyrwoll MJ, Kliesch S, Lopes AM, Goncalves J, Boyden SE, Wöste M, Hotaling JM, Nagirnaja L, Conrad DF, Carrell DT, Aston KI (2021) Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia. Hum Genet 140:217–227. https://doi.org/10.1007/s00439-020-02236-1
Scherthan H (2001) A bouquet makes ends meet. Nat Rev Mol Cell Biol 2:621–627. https://doi.org/10.1038/35085086
Scherthan H (2007) Telomere attachment and clustering during meiosis. Cell Mol Life Sci 64:117–124. https://doi.org/10.1007/s00018-006-6463-2
Scherthan H, Weich S, Schwegler H, Heyting C, Härle M, Cremer T (1996) Centromere and telomere movements during early meiotic prophase of mouse and man are associated with the onset of chromosome pairing. J Cell Biol 134:1109–1125. https://doi.org/10.1083/jcb.134.5.1109
Schober H, Ferreira H, Kalck V, Gehlen LR, Gasser SM (2009) Yeast telomerase and the SUN domain protein Mps3 anchor telomeres and repress subtelomeric recombination. Genes Dev 23:928–938. https://doi.org/10.1101/gad.1787509
Shibuya H, Hernandez-Hernandez A, Morimoto A, Negishi L, Hoog C, Watanabe Y (2015) MAJIN links telomeric DNA to the nuclear membrane by exchanging telomere cap. Cell 163:1252–1266. https://doi.org/10.1016/j.cell.2015.10.030
Starr DA, Fridolfsson HN (2010) Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges. Annu Rev Cell Dev Biol 26:421–444. https://doi.org/10.1146/annurev-cellbio-100109-104037
Wu H, Zhang X, Hua R, Li Y, Cheng L, Li K, Liu Y, Gao Y, Shen Q, Wang G, Lv M, Xu Y, He X, Cao Y, Liu MJ (2022) Homozygous missense mutation in CCDC155 disrupts the transmembrane distribution of CCDC155 and SUN1, resulting in non-obstructive azoospermia and premature ovarian insufficiency in humans. Hum Genet. https://doi.org/10.1007/s00439-022-02459-4
Wyrwoll MJ, van Walree ES, Hamer G, Rotte N, Motazacker MM, Meijers-Heijboer H, Alders M, Meißner A, Kaminsky E, Wöste M, Krallmann C, Kliesch S, Hunt TJ, Clark AT, Silber S, Stallmeyer B, Friedrich C, van Pelt AMM, Mathijssen IB, Tüttelmann F (2021) Bi-allelic variants in DNA mismatch repair proteins MutS homolog MSH4 and MSH5 cause infertility in both sexes. Hum Reprod 37:178–189. https://doi.org/10.1093/humrep/deab230
Xie C, Wang W, Tu C, Meng L, Lu G, Lin G, Lu LY, Tan YQ (2022) Meiotic recombination: insights into its mechanisms and its role in human reproduction with a special focus on non-obstructive azoospermia. Hum Reprod Update. https://doi.org/10.1093/humupd/dmac024
Yang C, Lin X, Ji Z, Huang Y, Zhang L, Luo J, Chen H, Li P, Tian R, Zhi E, Hong Y, Zhou Z, Zhang F, Li Z, Yao C (2022) Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia. Mol Hum Reprod. https://doi.org/10.1093/molehr/gaac021
Yao C, Yang C, Zhao L, Li P, Tian R, Chen H, Guo Y, Huang Y, Zhi E, Zhai J, Sun H, Zhang J, Hong Y, Zhang L, Ji Z, Zhang F, Zhou Z, Li Z (2021) Bi-allelic SHOC1 loss-of-function mutations cause meiotic arrest and non-obstructive azoospermia. J Med Genet 58:679–686. https://doi.org/10.1136/jmedgenet-2020-107042
Yatsenko A, Georgiadis A, Röpke A, Berman A, Jaffe T, Olszewska M, Westernströer B, Sanfilippo J, Kurpisz M, Rajkovic A, Yatsenko S, Kliesch S, Schlatt S, Tüttelmann FJT (2015) X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med 372:2097–2107. https://doi.org/10.1056/NEJMoa1406192
Yu X, Li M, Cai F, Yang S, Liu H, Zhang HJ (2021) TEX11A new mutation causes azoospermia and testicular meiotic arrest. Asian J Androl 23:510–515. https://doi.org/10.4103/aja.aja_8_21
Zhang Q, Tao C, Gao S, Li S, Xu B, Ke H, Wang Y, Zhang F, Qin Y, Zhang L, Guo T (2022) Homozygous variant in KASH5 causes premature ovarian insufficiency by disordered meiotic homologous pairing. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgac368
Zheng B, Zhao D, Zhang P, Shen C, Guo Y, Zhou T, Guo X, Zhou Z, Sha J (2015) Quantitative proteomics reveals the essential roles of stromal interaction molecule 1 (STIM1) in the testicular cord formation in mouse testis. Mol Cell Proteomics 14:2682–2691. https://doi.org/10.1074/mcp.M115.049569
Acknowledgements
We would like to thank the families that participated and supported this study.
Funding
This work was supported by the National Natural Science Foundation of China (82201762 and 82201765), the Natural Science Foundation of Jiangsu Province (BK20220200), the Suzhou Science and Technology Development Plan (LCZX202109), the Science and Technology Project of Changzhou (CJ20220143), and the Science and Technology Project of Jiangsu Health Committee (Z2021048).
Author information
Authors and Affiliations
Contributions
Conceptualization: TG, QZ, and HL. Methodology QM, BS, and DZ. Validation: QM, BS, and DZ. Formal analysis: QM, BS, and DZ. Resources: XF and JW. Data curation: JW. Writing—original draft preparation: QM. Writing—review and editing: TG, QZ, and HL. Visualization: XF. Supervision: HL. Project administration: QZ. Funding acquisition: QM, DZ, QZ, TG. All authors have read and agreed to the published version of the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Ethical approval
The study was conducted per the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Suzhou Municipal Hospital, China (No. 2020190).
Consent to participate
Informed consent was obtained from all subjects involved in the study. Written informed consent was obtained from the patient(s) to publish this paper.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Meng, Q., Shao, B., Zhao, D. et al. Loss of SUN1 function in spermatocytes disrupts the attachment of telomeres to the nuclear envelope and contributes to non-obstructive azoospermia in humans. Hum Genet 142, 531–541 (2023). https://doi.org/10.1007/s00439-022-02515-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-022-02515-z