Biallelic Variant in Cyclin B3 is Associated with Failure of Maternal Meiosis II and Recurrent Digynic Triploidy

Overview

Journal J Med Genet

Specialty Genetics

Date 2020 Sep 17

PMID 32938693

Citations 5

Authors

Nayeralsadat Fatemi

Najmeh Salehi

Laura Pignata

Pietro Palumbo

Maria Vittoria Cubellis

Fariba Ramazanali

Pierre Ray

Maryam Varkiani

Fakhreddin Reyhani-Sabet

Alireza Biglari

Angela Sparago

Basilia Acurzio

Orazio Palumbo

Massimo Carella

Andrea Riccio

Mehdi Totonchi

Affiliations

Soon will be listed here.

Abstract

Background: Triploidy is one of the most common chromosome abnormalities affecting human gestation and accounts for an important fraction of first-trimester miscarriages. Triploidy has been demonstrated in a few cases of recurrent pregnancy loss (RPL) but its molecular mechanisms are unknown. This study aims to identify the genetic cause of RPL associated with fetus triploidy.

Methods: We investigated genomic imprinting, genotyped sequence-tagged site (STS) markers and performed exome sequencing in a family including two sisters with RPL. Moreover, we evaluated oocyte maturation in vivo and in vitro and effect of the candidate protein variant in silico.

Results: While features of hydatidiform mole were excluded, the presence of triploidy of maternal origin was demonstrated in the fetuses. Oocyte maturation was deficient and all the maternally inherited pericentromeric STS alleles were homozygous in the fetuses. A deleterious missense variant (p.V1251D) of the cyclin B3 gene () affecting a residue conserved in placental mammals and located in a region that can interact with the cyclin-dependent kinase 1 or cyclin-dependent kinase 2 cosegregated in homozygosity with RPL.

Conclusion: Here, we report a family in which a damaging variant in cyclin B3 is associated with the failure of oocyte meiosis II and recurrent fetus triploidy, implicating a rationale for testing in RPL.

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References

Pergament E, Confino E, Zhang J, Roscetti L, Xien Chen P, Wellman D . Recurrent triploidy of maternal origin. Prenat Diagn. 2000; 20(7):561-3. DOI: 10.1002/1097-0223(200007)20:7<561::aid-pd875>3.0.co;2-1. View

Meng T, Lei W, Li J, Wang F, Zhao Z, Li A . Degradation of Ccnb3 is essential for maintenance of MII arrest in oocyte. Biochem Biophys Res Commun. 2019; 521(1):265-269. DOI: 10.1016/j.bbrc.2019.10.124. View

Khawajkie Y, Buckett W, Nguyen N, Mechtouf N, Ao A, Arseneau J . Recurrent triploid digynic conceptions and mature ovarian teratomas: Are they different manifestations of the same genetic defect?. Genes Chromosomes Cancer. 2017; 56(12):832-840. DOI: 10.1002/gcc.22484. View

Kim B, Lee S, Kim K, Han C, Kim J . In vitro maturation, fertilization, and development of human germinal vesicle oocytes collected from stimulated cycles. Fertil Steril. 2000; 74(6):1153-8. DOI: 10.1016/s0015-0282(00)01617-4. View

Brown N, Lowe E, Petri E, Skamnaki V, Antrobus R, Johnson L . Cyclin B and cyclin A confer different substrate recognition properties on CDK2. Cell Cycle. 2007; 6(11):1350-9. DOI: 10.4161/cc.6.11.4278. View

Li Y, Wang L, Zhang L, He Z, Feng G, Sun H . Cyclin B3 is required for metaphase to anaphase transition in oocyte meiosis I. J Cell Biol. 2019; 218(5):1553-1563. PMC: 6504906. DOI: 10.1083/jcb.201808088. View

Karasu M, Bouftas N, Keeney S, Wassmann K . Cyclin B3 promotes anaphase I onset in oocyte meiosis. J Cell Biol. 2019; 218(4):1265-1281. PMC: 6446836. DOI: 10.1083/jcb.201808091. View

Soler A, Morales C, Mademont-Soler I, Margarit E, Borrell A, Borobio V . Overview of Chromosome Abnormalities in First Trimester Miscarriages: A Series of 1,011 Consecutive Chorionic Villi Sample Karyotypes. Cytogenet Genome Res. 2017; 152(2):81-89. DOI: 10.1159/000477707. View

Wolgemuth D . Function of cyclins in regulating the mitotic and meiotic cell cycles in male germ cells. Cell Cycle. 2008; 7(22):3509-13. PMC: 4080918. DOI: 10.4161/cc.7.22.6978. View

10.

Kang H, Rosenwaks Z . Triploidy--the breakdown of monogamy between sperm and egg. Int J Dev Biol. 2008; 52(5-6):449-54. DOI: 10.1387/ijdb.082602hk. View

11.

Hatirnaz S, Ata B, Hatirnaz E, Dahan M, Tannus S, Tan J . Oocyte maturation: A sytematic review. Turk J Obstet Gynecol. 2018; 15(2):112-125. PMC: 6022428. DOI: 10.4274/tjod.23911. View

12.

Lozano J, Perret E, Schatt P, Arnould C, Peaucellier G, Picard A . Molecular cloning, gene localization, and structure of human cyclin B3. Biochem Biophys Res Commun. 2002; 291(2):406-13. DOI: 10.1006/bbrc.2002.6458. View

13.

Polat S, Karaburgu S, Unluhizarci K, Dundar M, Ozkul Y, Arslan Y . The role of androgen receptor CAG repeat polymorphism in androgen excess disorder and idiopathic hirsutism. J Endocrinol Invest. 2020; 43(9):1271-1281. DOI: 10.1007/s40618-020-01215-7. View

14.

Rodrigues C, Pires D, Ascher D . DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res. 2018; 46(W1):W350-W355. PMC: 6031064. DOI: 10.1093/nar/gky300. View

15.

Park S, Jung E, Ryu R, Kang H, Ko J, Kim H . Clinical implementation of whole-genome array CGH as a first-tier test in 5080 pre and postnatal cases. Mol Cytogenet. 2011; 4:12. PMC: 3114015. DOI: 10.1186/1755-8166-4-12. View

16.

Stephenson M, Kutteh W . Evaluation and management of recurrent early pregnancy loss. Clin Obstet Gynecol. 2007; 50(1):132-45. DOI: 10.1097/GRF.0b013e31802f1c28. View

17.

Li T, Makris M, Tomsu M, Tuckerman E, Laird S . Recurrent miscarriage: aetiology, management and prognosis. Hum Reprod Update. 2002; 8(5):463-81. DOI: 10.1093/humupd/8.5.463. View

18.

Chapman R, Reading B, Sullivan C . Ovary transcriptome profiling via artificial intelligence reveals a transcriptomic fingerprint predicting egg quality in striped bass, Morone saxatilis. PLoS One. 2014; 9(5):e96818. PMC: 4018430. DOI: 10.1371/journal.pone.0096818. View

19.

Deyter G, Furuta T, Kurasawa Y, Schumacher J . Caenorhabditis elegans cyclin B3 is required for multiple mitotic processes including alleviation of a spindle checkpoint-dependent block in anaphase chromosome segregation. PLoS Genet. 2010; 6(11):e1001218. PMC: 2991249. DOI: 10.1371/journal.pgen.1001218. View

20.

Gallant P, Nigg E . Identification of a novel vertebrate cyclin: cyclin B3 shares properties with both A- and B-type cyclins. EMBO J. 1994; 13(3):595-605. PMC: 394849. DOI: 10.1002/j.1460-2075.1994.tb06297.x. View