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, GO Sgene, Berta Crespo, Nadjeda Moreno, Paola Niola, Tony Brooks, Caroline E. Brain, Mehul T. Dattani, Daniel KelbermanRoser Vento-Tormo, Carlos F. Lagos, Gabriel Livera, Gerard S. Conway, John C. Achermann

*Autor correspondiente de este trabajo

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

16 Citas (Scopus)

Resumen

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.

Idioma originalInglés
Número de artículoe154671
PublicaciónJCI Insight
Volumen7
N.º5
DOI
EstadoPublicada - 2022

Nota bibliográfica

Publisher Copyright:
© 2022, McGlacken-Byrne et al.

Áreas temáticas de ASJC Scopus

  • Medicina General

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