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Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes

European Journal of Human Genetics volume 30, pages 219–228 (2022) Cite this article

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Abstract

Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis.

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Fig. 1: Diagram depicting proteins involved in meiosis.
The alternative text for this image may have been generated using AI.
Fig. 2: WES identifies REC8 as a novel meiosis gene underlying human POI.
The alternative text for this image may have been generated using AI.
Fig. 3: WES identifies HROB as a novel meiosis gene underlying human POI.
The alternative text for this image may have been generated using AI.

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Data availability

The full WES datasets generated during the current study are not publicly available due to their potential to impinge patient anonymity, but are available from the corresponding author on reasonable request. The variants described within the text are available in the ClinVar repository (https://www.ncbi.nlm.nih.gov/clinvar/).

References

  1. Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH. Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic spectrum. Endocr Rev. 2016;37:609–35.

    Article  Google Scholar 

  2. Conway GS, Payne NN, Webb J, Murray A, Jacobs PA. Fragile X premutation screening in women with premature ovarian failure. Hum Reprod. 1998;13:1184–7.

    Article  CAS  Google Scholar 

  3. Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod update. 2015;21:787–808.

    Article  CAS  Google Scholar 

  4. European Society for Human Reproduction; Embryology Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Human reproduction. 2016;31:926–37.

  5. Tucker EJ, Grover SR, Robevska G, van den Bergen J, Hanna C, Sinclair AH. Identification of variants in pleiotropic genes causing “isolated” premature ovarian insufficiency: implications for medical practice. Eur J Hum Genet: EJHG. 2018;26:1319–28.

    Article  CAS  Google Scholar 

  6. Goldberg Y, Halpern N, Hubert A, Adler SN, Cohen S, Plesser-Duvdevani M, et al. Mutated MCM9 is associated with predisposition to hereditary mixed polyposis and colorectal cancer in addition to primary ovarian failure. Cancer Genet. 2015;208:621–4.

    Article  CAS  Google Scholar 

  7. Hollingsworth NM. A new role for the synaptonemal complex in the regulation of meiotic recombination. Genes Dev. 2020;34:1562–4.

    Article  CAS  Google Scholar 

  8. Lacombe A, Lee H, Zahed L, Choucair M, Muller JM, Nelson SF, et al. Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure. Am J Hum Genet. 2006;79:113–9.

    Article  CAS  Google Scholar 

  9. Freudenreich CH, Su XA. Relocalization of DNA lesions to the nuclear pore complex. FEMS Yeast Res. 2016;16:fow095.

    Article  Google Scholar 

  10. Hustedt N, Saito Y, Zimmermann M, Alvarez-Quilon A, Setiaputra D, Adam S, et al. Control of homologous recombination by the HROB-MCM8-MCM9 pathway. Genes Dev. 2019;33:1397–415.

    Article  CAS  Google Scholar 

  11. Takata K, Reh S, Tomida J, Person MD, Wood RD. Human DNA helicase HELQ participates in DNA interstrand crosslink tolerance with ATR and RAD51 paralogs. Nat Commun. 2013;4:2338.

    Article  Google Scholar 

  12. Hoffmann ER, Borts RH. Meiotic recombination intermediates and mismatch repair proteins. Cytogenetic genome Res. 2004;107:232–48.

    Article  CAS  Google Scholar 

  13. Manhart CM, Alani E. Roles for mismatch repair family proteins in promoting meiotic crossing over. DNA repair. 2016;38:84–93.

    Article  CAS  Google Scholar 

  14. Guiraldelli MF, Eyster C, Wilkerson JL, Dresser ME, Pezza RJ. Mouse HFM1/Mer3 is required for crossover formation and complete synapsis of homologous chromosomes during meiosis. PLoS Genet. 2013;9:e1003383.

    Article  CAS  Google Scholar 

  15. Crismani W, Girard C, Froger N, Pradillo M, Santos JL, Chelysheva L, et al. FANCM limits meiotic crossovers. Science. 2012;336:1588–90.

    Article  CAS  Google Scholar 

  16. Porcu E, Cillo GM, Cipriani L, Sacilotto F, Notarangelo L, Damiano G, et al. Impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes in young women with breast cancer. J Assist Reprod Genet. 2020;37:709–15.

    Article  Google Scholar 

  17. Tao XY, Zuo AZ, Wang JQ, Tao FB. Effect of primary ovarian insufficiency and early natural menopause on mortality: a meta-analysis. Climacteric: J Int Menopause Soc. 2016;19:27–36.

    Article  Google Scholar 

  18. ESHR, Embryology Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31:926–37.

    Article  Google Scholar 

  19. Sadedin SP, Dashnow H, James PA, Bahlo M, Bauer DC, Lonie A, et al. Cpipe: a shared variant detection pipeline designed for diagnostic settings. Genome Med. 2015;7:68.

    Article  Google Scholar 

  20. Lindeboom RG, Supek F, Lehner B. The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet. 2016;48:1112–8.

    Article  CAS  Google Scholar 

  21. AlAsiri S, Basit S, Wood-Trageser MA, Yatsenko SA, Jeffries EP, Surti U, et al. Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Investig. 2015;125:258–62.

    Article  Google Scholar 

  22. Heddar A, Beckers D, Fouquet B, Roland D, Misrahi M. A novel phenotype combining primary ovarian insufficiency growth retardation and pilomatricomas with MCM8 mutation. J Clin Endocrinol Metab. 2020;105:dgaa155.

    Article  Google Scholar 

  23. Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, Surti U, et al. MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet. 2014;95:754–62.

    Article  CAS  Google Scholar 

  24. Jaillard S, McElreavy K, Robevska G, Akloul L, Ghieh F, Sreenivasan R, et al. STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia. Mol Hum Reprod. 2020;26:665–77.

    Article  CAS  Google Scholar 

  25. Heddar A, Dessen P, Flatters D, Misrahi M. Novel STAG3 mutations in a Caucasian family with primary ovarian insufficiency. Mol Genet Genomics. 2019;294:1527–34.

    Article  CAS  Google Scholar 

  26. Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL, Oka K, et al. Mutant cohesin in premature ovarian failure. N. Engl J Med. 2014;370:943–9.

    Article  CAS  Google Scholar 

  27. Padovano V, Lucibello I, Alari V, Della Mina P, Crespi A, Ferrari I, et al. The POF1B candidate gene for premature ovarian failure regulates epithelial polarity. J Cell Sci. 2011;124:3356–68.

    Article  CAS  Google Scholar 

  28. Ledig S, Preisler-Adams S, Morlot S, Liehr T, Wieacker P. Premature ovarian failure caused by a heterozygous missense mutation in POF1B and a reciprocal translocation 46,X,t(X;3)(q21.1;q21.3). Sex Dev: Genet, Mol Biol, evolution, Endocrinol, Embryol, Pathol sex Determ Differ. 2015;9:86–90.

    Article  CAS  Google Scholar 

  29. Ren Y, Diao F, Katari S, Yatsenko S, Jiang H, Wood-Trageser MA, et al. Functional study of a novel missense single-nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency. Mol Genet Genom Med. 2018;6:276–81.

    Article  CAS  Google Scholar 

  30. Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsunaga S, Shiina M, et al. Biallelic mutations in nuclear pore complex subunit NUP107 cause early-childhood-onset steroid-resistant nephrotic syndrome. Am J Hum Genet. 2015;97:555–66.

    Article  CAS  Google Scholar 

  31. Rosti RO, Sotak BN, Bielas SL, Bhat G, Silhavy JL, Aslanger AD, et al. Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome. J Med Genet. 2017;54:399–403.

    Article  CAS  Google Scholar 

  32. Weinberg-Shukron A, Renbaum P, Kalifa R, Zeligson S, Ben-Neriah Z, Dreifuss A, et al. A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis. J Clin Investig. 2015;125:4295–304.

    Article  Google Scholar 

  33. Wang J, Zhang W, Jiang H, Wu BL. Primary ovarian insufficiency C: mutations in HFM1 in recessive primary ovarian insufficiency. N. Engl J Med. 2014;370:972–4.

    Article  CAS  Google Scholar 

  34. Cheng JM, Liu YX. Age-related loss of cohesion: causes and effects. Int J Mol Sci. 2017;18:1578.

    Article  Google Scholar 

  35. Fukuda T, Fukuda N, Agostinho A, Hernandez-Hernandez A, Kouznetsova A, Hoog C. STAG3-mediated stabilization of REC8 cohesin complexes promotes chromosome synapsis during meiosis. EMBO J. 2014;33:1243–55.

    Article  CAS  Google Scholar 

  36. Xu H, Beasley MD, Warren WD, van der Horst GT, McKay MJ. Absence of mouse REC8 cohesin promotes synapsis of sister chromatids in meiosis. Developmental Cell. 2005;8:949–61.

    Article  CAS  Google Scholar 

  37. Bannister LA, Reinholdt LG, Munroe RJ, Schimenti JC. Positional cloning and characterization of mouse mei8, a disrupted allelle of the meiotic cohesin Rec8. Genesis. 2004;40:184–94.

    Article  CAS  Google Scholar 

  38. Tucker EJ, Jaillard S, Grover SR, van den Bergen J, Robevska G, Bell KM, et al. TP63-truncating variants cause isolated premature ovarian insufficiency. Hum Mutat. 2019;40:886–92.

    CAS  PubMed  Google Scholar 

  39. Bouilly J, Beau I, Barraud S, Bernard V, Azibi K, Fagart J, et al. Identification of multiple gene mutations accounts for a new genetic architecture of primary ovarian insufficiency. J Clin Endocrinol Metab. 2016;101:4541–50.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by an NHMRC program (1074258, to AHS), NHMRC fellowships (1054432 to EJT, 1126995 to RS, 1062854 to AHS) and a Melbourne Research Scholarship (to SB) and was supported by the Victorian Government’s Operational Infrastructure Support Program and a CHU Rennes grant (Appel à Projets Innovations 2019 to SJ). We thank the Bioinformatic department of CHU Rennes (UF Bioinformatique et Génétique Computationnelle, Service de Génétique Moléculaire et Génomique, Pr M. De Tayrac) for helpful advice and technical assistance. Some figures were created with BioRender.com.

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Author notes

  1. These authors jointly supervised this work: Sylvie Jaillard, Andrew H. Sinclair.

Authors and Affiliations

  1. Murdoch Children’s Research Institute, Melbourne, VIC, Australia

    Elena J. Tucker, Katrina M. Bell, Gorjana Robevska, Jocelyn van den Bergen, Katie L. Ayers, Nurin Listyasari, Shabnam Bakhshalizadeh, Rajini Sreenivasan & Andrew H. Sinclair

  2. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia

    Elena J. Tucker, Katie L. Ayers, Shabnam Bakhshalizadeh, Rajini Sreenivasan & Andrew H. Sinclair

  3. Division of Human Genetics, Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University/Diponegoro National Hospital, Semarang, Indonesia

    Nurin Listyasari & Sultana MH Faradz

  4. Department of Endocrinology and Reproductive Medicine, AP‐HP, Sorbonne University Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Centre des Pathologies Gynécologiques Rares, Paris, France

    Jérôme Dulon & Philippe Touraine

  5. CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, F-35033, Rennes, France

    Benedicte Nouyou, Marc-Antoine Belaud-Rotureau & Sylvie Jaillard

  6. CHU Rennes, UF Bioinformatique et Génétique Computationnelle, Service de Génétique Moléculaire et Génomique, F-35033, Rennes, France

    Wilfrid Carre

  7. CHU Rennes, Service de Génétique Clinique, CLAD Ouest, F-35033, Rennes, France

    Linda Akloul

  8. CHU Rennes, Département de Gynécologie Obstétrique et Reproduction Humaine, F-35033, Rennes, France

    Solène Duros & Mathilde Domin-Bernhard

  9. Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) – UMR_S 1085, F-35000, Rennes, France

    Marc-Antoine Belaud-Rotureau & Sylvie Jaillard

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  1. Elena J. Tucker
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Contributions

EJT, SJ, PT and AHS contributed to conception and design of the study. All authors contributed to the acquisition and/or analysis of data. EJT and SJ wrote the manuscript. All authors revised it critically and approved the final version.

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Correspondence to Elena J. Tucker or Sylvie Jaillard.

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The authors declare no competing interests.

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Written informed consent was obtained from all participants. All procedures were approved by the Ethics Committee of Rennes University Hospital and the French law (CCTIRS Comité Consultatif sur le Traitement de l’Information en matière de Recherche dans le domaine de la Santé) or the Human Research Ethics Committee of the Royal Children’s Hospital, Melbourne (HREC/22073).

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Tucker, E.J., Bell, K.M., Robevska, G. et al. Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes. Eur J Hum Genet 30, 219–228 (2022). https://doi.org/10.1038/s41431-021-00977-9

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