McGlacken-Byrne, Sinead M;
del Valle, Ignacio;
Stabej, Polona Le Quesne;
Bellutti, Laura;
Garcia-Alonso, Luz;
Ocaka, Louise A;
Ishida, Miho;
... Achermann, John C; + view all
(2022)
Pathogenic variants in the human m(6)A reader YTHDC2 are associated with primary ovarian insufficiency.
JCI Insight
, 7
(5)
, Article e154671. 10.1172/jci.insight.154671.
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Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency.pdf - Other Download (7MB) | Preview |
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 meiosisassociated 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.
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