Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency.

Sinead Mcglacken-Byrne ,Berta Crespo,Gabriel Livera,Andrey Gagunashvili,John C Achermann,Paola Niola,Carlos F Lagos,Talisa Mistry,Ignacio Del Valle,Laura Bellutti,Jenifer P Suntharalingham,Polona Le Quesne Stabej,Tony Brooks,Federica Buonocore,Miho Ishida,Daniel Kelberman,Gerard S Conway,Nadjeda Moreno,Mehul Dattani ,Luz Garcia‐Alonso ,Olumide Ogunbiyi ,Caroline Brain ,Roser Vento‐Tormo ,Louise Ocaka

doi:10.1172/jci.insight.154671

Abstract

Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: c. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosis-associated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377* variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI.

Highlights

Primary ovarian insufficiency (POI) affects 1% of women and is characterized by early loss of normal ovarian function and depletion of the ovarian reserve [1]
Our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI
We provide evidence that the m6A reader YTHDC2 plays a role in the regulation of meiosis and human gonadal development and, for the first time to our knowledge, show that loss of function in YTHDC2 is associated with POI

Summary

Introduction

Primary ovarian insufficiency (POI) affects 1% of women and is characterized by early loss of normal ovarian function and depletion of the ovarian reserve [1]. While most women with POI present with secondary amenorrhea, approximately 10% present with primary amenorrhea with or without absent puberty [3]. Many of the remaining affected women may have an underlying genetic cause. This hypothesis is supported by the high incidence of familial POI, the increased incidence of POI within consanguineous pedigrees, and the association of POI with multisystem syndromes [6–9]. Next-generation sequencing has implicated variants in approximately 60 genes in the molecular pathogenesis of POI [6, 8]. Further genes have been implicated in female fertility using transgenic mouse models. This, along with the fact that up to 80% of “idiopathic” POI remains unexplained, suggests that other biologically significant genetic causes of POI are yet to be identified [3]

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Results

Conclusion