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Pathogenic variants in the human m(6)A reader YTHDC2 are associated with primary ovarian insufficiency

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. Green open access

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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.

Type: Article
Title: Pathogenic variants in the human m(6)A reader YTHDC2 are associated with primary ovarian insufficiency
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/jci.insight.154671
Publisher version: https://doi.org/10.1172/jci.insight.154671
Language: English
Additional information: Copyright: © 2022, McGlacken-Byrne et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
Keywords: Science & Technology, Life Sciences & Biomedicine, Medicine, Research & Experimental, Research & Experimental Medicine, PROTEIN, EXPRESSION, TRANSCRIPTOME, MEIOSIS, DYNAMICS, PROGRAM, COMPLEX, CANCER, DOMAIN, CELLS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
URI: https://discovery.ucl.ac.uk/id/eprint/10147264
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