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 Kelberman; Roser Vento-Tormo; Carlos F. Lagos; Gabriel Livera; Gerard S. Conway; John C. Achermann

doi:10.1172/jci.insight.154671

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English
Article number	e154671
Journal	JCI Insight
Volume	7
Issue number	5
DOIs	https://doi.org/10.1172/jci.insight.154671
State	Published - 2022

Bibliographical note

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

ASJC Scopus subject areas

General Medicine

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10.1172/jci.insight.154671

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McGlacken-Byrne, S. M., del Valle, I., Stabej, P. L. Q., Bellutti, L., Garcia-Alonso, L., Ocaka, L. A., Ishida, M., Suntharalingham, J. P., Gagunashvili, A., Ogunbiyi, O. K., Mistry, T., Buonocore, F., Sgene, GO., Crespo, B., Moreno, N., Niola, P., Brooks, T., Brain, C. E., Dattani, M. T., ... Achermann, J. C. (2022). Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency. JCI Insight, 7(5), Article e154671. https://doi.org/10.1172/jci.insight.154671

@article{3852efc5d4414befaa319cbd686b9b1f,

title = "Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency",

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.",

author = "McGlacken-Byrne, {Sin{\'e}ad M.} and {del Valle}, Ignacio and Stabej, {Polona Le Quesne} and Laura Bellutti and Luz Garcia-Alonso and Ocaka, {Louise A.} and Miho Ishida and Suntharalingham, {Jenifer P.} and Andrey Gagunashvili and Ogunbiyi, {Olumide K.} and Talisa Mistry and Federica Buonocore and GO Sgene and Berta Crespo and Nadjeda Moreno and Paola Niola and Tony Brooks and Brain, {Caroline E.} and Dattani, {Mehul T.} and Daniel Kelberman and Roser Vento-Tormo and Lagos, {Carlos F.} and Gabriel Livera and Conway, {Gerard S.} and Achermann, {John C.}",

note = "Publisher Copyright: {\textcopyright} 2022, McGlacken-Byrne et al.",

year = "2022",

month = mar,

day = "8",

doi = "10.1172/jci.insight.154671",

language = "English",

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McGlacken-Byrne, SM, del Valle, I, Stabej, PLQ, Bellutti, L, Garcia-Alonso, L, Ocaka, LA, Ishida, M, Suntharalingham, JP, Gagunashvili, A, Ogunbiyi, OK, Mistry, T, Buonocore, F, Sgene, GO, Crespo, B, Moreno, N, Niola, P, Brooks, T, Brain, CE, Dattani, MT, Kelberman, D, Vento-Tormo, R, Lagos, CF, Livera, G, Conway, GS & Achermann, JC 2022, 'Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency', JCI Insight, vol. 7, no. 5, e154671. https://doi.org/10.1172/jci.insight.154671

TY - JOUR

T1 - Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency

AU - McGlacken-Byrne, Sinéad M.

AU - del Valle, Ignacio

AU - Stabej, Polona Le Quesne

AU - Bellutti, Laura

AU - Garcia-Alonso, Luz

AU - Ocaka, Louise A.

AU - Ishida, Miho

AU - Suntharalingham, Jenifer P.

AU - Gagunashvili, Andrey

AU - Ogunbiyi, Olumide K.

AU - Mistry, Talisa

AU - Buonocore, Federica

AU - Sgene, GO

AU - Crespo, Berta

AU - Moreno, Nadjeda

AU - Niola, Paola

AU - Brooks, Tony

AU - Brain, Caroline E.

AU - Dattani, Mehul T.

AU - Kelberman, Daniel

AU - Vento-Tormo, Roser

AU - Lagos, Carlos F.

AU - Livera, Gabriel

AU - Conway, Gerard S.

AU - Achermann, John C.

PY - 2022/3/8

Y1 - 2022/3/8

N2 - 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.

AB - 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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U2 - 10.1172/jci.insight.154671

DO - 10.1172/jci.insight.154671

M3 - Article

C2 - 35138268

AN - SCOPUS:85125927624

SN - 2379-3708

VL - 7

JO - JCI Insight

JF - JCI Insight

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ER -

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

Abstract

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