Meiotic Cohesin and Variants Associated With Human Reproductive Aging and Disease.

Rachel Beverley,Meredith L Snook,Miguel Angel Brieño-Enríquez

doi:10.3389/fcell.2021.710033

Abstract

Successful human reproduction relies on the well-orchestrated development of competent gametes through the process of meiosis. The loading of cohesin, a multi-protein complex, is a key event in the initiation of mammalian meiosis. Establishment of sister chromatid cohesion via cohesin rings is essential for ensuring homologous recombination-mediated DNA repair and future proper chromosome segregation. Cohesin proteins loaded during female fetal life are not replenished over time, and therefore are a potential etiology of age-related aneuploidy in oocytes resulting in decreased fecundity and increased infertility and miscarriage rates with advancing maternal age. Herein, we provide a brief overview of meiotic cohesin and summarize the human genetic studies which have identified genetic variants of cohesin proteins and the associated reproductive phenotypes including primary ovarian insufficiency, trisomy in offspring, and non-obstructive azoospermia. The association of cohesion defects with cancer predisposition and potential impact on aging are also described. Expansion of genetic testing within clinical medicine, with a focus on cohesin protein-related genes, may provide additional insight to previously unknown etiologies of disorders contributing to gamete exhaustion in females, and infertility and reproductive aging in both men and women.

Highlights

Infertility, a disease defined by the failure to achieve a successful pregnancy after 12 or more months of regular, unprotected intercourse or due to an impairment of a person’s capacity to reproduce (Practice Committee of the American Society for Reproductive Medicine, 2020), is estimated to affect approximately 15% of the reproductive age population
This review provides an overview of meiotic cohesin and summarizes the human genetic studies that have identified genetic variants of cohesin proteins and the associated reproductive phenotypes
In the review of the literature outlined above for women with Primary ovarian insufficiency (POI) and associated STAG3 variants, there was one patient noted to have bilateral ovarian tumors diagnosed at age 19 which consisted of a gonadoblastoma on the right ovary and a complex tumor of the left ovary consisting of embryonal carcinoma, choriocarcinoma, and dysgerminoma (Caburet et al, 2014)

Summary

Introduction

Infertility, a disease defined by the failure to achieve a successful pregnancy after 12 or more months of regular, unprotected intercourse or due to an impairment of a person’s capacity to reproduce (Practice Committee of the American Society for Reproductive Medicine, 2020), is estimated to affect approximately 15% of the reproductive age population. It is likely that deterioration of the complex of proteins involved in chromosome cohesion, referred to as cohesin proteins, or genetic variants affecting these proteins are potential drivers of age-related infertility and aneuploidy.

Results

Conclusion