Pathogenic Variants of Meiotic Double Strand Break (DSB) Formation Genes PRDM9 and ANKRD31 in Premature Ovarian Insufficiency

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2021 Jul 14

PMID 34257419

Citations 8

Authors

Yiyang Wang

Ting Guo

Hanni Ke

Qian Zhang

Shan Li

Wei Luo

Yingying Qin

Affiliations

Soon will be listed here.

Abstract

Purpose: The etiology of premature ovarian insufficiency (POI) is heterogeneous, and genetic factors account for 20-25% of the patients. The primordial follicle pool is determined by the meiosis process, which is initiated by programmed DNA double strand breaks (DSB) and homologous recombination. The objective of the study is to explore the role of DSB formation genes in POI pathogenesis.

Methods: Variants in DSB formation genes were analyzed from a database of exome sequencing in 1,030 patients with POI. The pathogenic effects of the potentially causative variants were verified by further functional studies.

Results: Three pathogenic heterozygous variants in PRDM9 and two in ANKRD31 were identified in seven patients. Functional studies showed the variants in PRDM9 impaired its methyltransferase activity, and the ANKRD31 variations disturbed its interaction with another DSB formation factor REC114 by haploinsufficiency effect, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent.

Conclusion: Our study identified pathogenic variants of PRDM9 and ANKRD31 in POI patients, shedding new light on the contribution of meiotic DSB formation genes in ovarian development, further expanding the genetic architecture of POI.

Citing Articles

Primary ovarian insufficiency: update on clinical and genetic findings.

Federici S, Rossetti R, Moleri S, Munari E, Frixou M, Bonomi M Front Endocrinol (Lausanne). 2024; 15:1464803.

PMID: 39391877 PMC: 11466302. DOI: 10.3389/fendo.2024.1464803.

Bi-allelic missense variants in MEI4 cause preimplantation embryonic arrest and female infertility.

Pan Z, Wang W, Wu L, Yao Z, Wang W, Chen Y Hum Genet. 2024; 143(9-10):1049-1060.

PMID: 38252283 DOI: 10.1007/s00439-023-02633-2.

Natural variation in the zinc-finger-encoding exon of Prdm9 affects hybrid sterility phenotypes in mice.

AbuAlia K, Damm E, Ullrich K, Mukaj A, Parvanov E, Forejt J Genetics. 2024; 226(3).

PMID: 38217871 PMC: 10917509. DOI: 10.1093/genetics/iyae004.

Essential roles of the ANKRD31-REC114 interaction in meiotic recombination and mouse spermatogenesis.

Xu J, Li T, Kim S, Boekhout M, Keeney S Proc Natl Acad Sci U S A. 2023; 120(47):e2310951120.

PMID: 37976262 PMC: 10666023. DOI: 10.1073/pnas.2310951120.

Synaptonemal Complex in Human Biology and Disease.

Llano E, Pendas A Cells. 2023; 12(13).

PMID: 37443752 PMC: 10341275. DOI: 10.3390/cells12131718.

References

Jiao X, Ke H, Qin Y, Chen Z . Molecular Genetics of Premature Ovarian Insufficiency. Trends Endocrinol Metab. 2018; 29(11):795-807. DOI: 10.1016/j.tem.2018.07.002. View

Kappeler C, Hoyer P . 4-vinylcyclohexene diepoxide: a model chemical for ovotoxicity. Syst Biol Reprod Med. 2012; 58(1):57-62. PMC: 3307534. DOI: 10.3109/19396368.2011.648820. View

De Vos M, Devroey P, Fauser B . Primary ovarian insufficiency. Lancet. 2010; 376(9744):911-21. DOI: 10.1016/S0140-6736(10)60355-8. View

Alasiri S, Basit S, Wood-Trageser M, Yatsenko S, Jeffries E, Surti U . Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest. 2014; 125(1):258-62. PMC: 4382257. DOI: 10.1172/JCI78473. View

Powers N, Dumont B, Emori C, Lawal R, Brunton C, Paigen K . Sexual dimorphism in the meiotic requirement for PRDM9: A mammalian evolutionary safeguard. Sci Adv. 2020; 6(43). PMC: 7608834. DOI: 10.1126/sciadv.abb6606. View

Franca M, Nishi M, Funari M, Lerario A, Baracat E, Hayashida S . Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency. Eur J Med Genet. 2018; 62(3):186-189. DOI: 10.1016/j.ejmg.2018.07.008. View

Desai S, Wood-Trageser M, Matic J, Chipkin J, Jiang H, Bachelot A . MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency. J Clin Endocrinol Metab. 2016; 102(2):576-582. PMC: 5413161. DOI: 10.1210/jc.2016-2565. View

Wood-Trageser M, Gurbuz F, Yatsenko S, Jeffries E, Kotan L, Surti U . MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet. 2014; 95(6):754-62. PMC: 4259971. DOI: 10.1016/j.ajhg.2014.11.002. View

Luo W, Guo T, Li G, Liu R, Zhao S, Song M . Variants in Homologous Recombination Genes EXO1 and RAD51 Related with Premature Ovarian Insufficiency. J Clin Endocrinol Metab. 2020; 105(10). DOI: 10.1210/clinem/dgaa505. View

10.

Fakhro K, Elbardisi H, Arafa M, Robay A, Rodriguez-Flores J, Al-Shakaki A . Point-of-care whole-exome sequencing of idiopathic male infertility. Genet Med. 2018; 20(11):1365-1373. DOI: 10.1038/gim.2018.10. View

11.

Bolcun-Filas E, Handel M . Meiosis: the chromosomal foundation of reproduction. Biol Reprod. 2018; 99(1):112-126. DOI: 10.1093/biolre/ioy021. View

12.

Kneitz B, Cohen P, Avdievich E, Zhu L, Kane M, Hou Jr H . MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev. 2000; 14(9):1085-97. PMC: 316572. View

13.

Brick K, Smagulova F, Khil P, Camerini-Otero R, Petukhova G . Genetic recombination is directed away from functional genomic elements in mice. Nature. 2012; 485(7400):642-5. PMC: 3367396. DOI: 10.1038/nature11089. View

14.

Bouilly J, Beau I, Barraud S, Bernard V, Azibi K, Fagart J . Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency. J Clin Endocrinol Metab. 2016; 101(12):4541-4550. DOI: 10.1210/jc.2016-2152. View

15.

Huang T, Yuan S, Gao L, Li M, Yu X, Zhan J . The histone modification reader ZCWPW1 links histone methylation to PRDM9-induced double-strand break repair. Elife. 2020; 9. PMC: 7314539. DOI: 10.7554/eLife.53459. View

16.

Luo M, Yang F, Leu N, Landaiche J, Handel M, Benavente R . MEIOB exhibits single-stranded DNA-binding and exonuclease activities and is essential for meiotic recombination. Nat Commun. 2013; 4:2788. PMC: 3891831. DOI: 10.1038/ncomms3788. View

17.

Qin Y, Jiao X, Simpson J, Chen Z . Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015; 21(6):787-808. PMC: 4594617. DOI: 10.1093/humupd/dmv036. View

18.

Guo T, Zhao S, Zhao S, Chen M, Li G, Jiao X . Mutations in MSH5 in primary ovarian insufficiency. Hum Mol Genet. 2017; 26(8):1452-1457. PMC: 5393145. DOI: 10.1093/hmg/ddx044. View

19.

Papanikos F, Clement J, Testa E, Ravindranathan R, Grey C, Dereli I . Mouse ANKRD31 Regulates Spatiotemporal Patterning of Meiotic Recombination Initiation and Ensures Recombination between X and Y Sex Chromosomes. Mol Cell. 2019; 74(5):1069-1085.e11. DOI: 10.1016/j.molcel.2019.03.022. View

20.

Baudat F, Imai Y, de Massy B . Meiotic recombination in mammals: localization and regulation. Nat Rev Genet. 2013; 14(11):794-806. DOI: 10.1038/nrg3573. View