JCI Insight (Mar 2022)

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

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

Journal volume & issue
Vol. 7, no. 5

Abstract

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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.

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