2. Academic Validation
  3. Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency

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

  • JCI Insight. 2022 Mar 8;7(5):e154671. doi: 10.1172/jci.insight.154671.
Sinéad M McGlacken-Byrne 1 2 3,  Ignacio Del Valle 1,  Polona Le Quesne Stabej 4 5,  Laura Bellutti 6,  Luz Garcia-Alonso 7,  Louise A Ocaka 4,  Miho Ishida 1,  Jenifer P Suntharalingham 1,  Andrey Gagunashvili 4,  Olumide K Ogunbiyi 8 9,  Talisa Mistry 8 9,  Federica Buonocore 1,  GOSgene,  Berta Crespo 9,  Nadjeda Moreno 9,  Paola Niola 10,  Tony Brooks 10,  Caroline E Brain 2,  Mehul T Dattani 1 2,  Daniel Kelberman 4,  Roser Vento-Tormo 7,  Carlos F Lagos 11,  Gabriel Livera 6,  Gerard S Conway 3,  John C Achermann 1
Affiliations

Affiliations

  • 1 Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
  • 2 Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom.
  • 3 EGA Institute for Women's Health, University College London, London, United Kingdom.
  • 4 GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
  • 5 Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
  • 6 Laboratory of Development of the Gonads, Genetic Stability Stem Cells and Radiations, CEA/IBFJ/iRCM, University of Paris-Saclay, University Paris City, Fontenay aux Roses, France.
  • 7 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
  • 8 Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
  • 9 Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
  • 10 UCL Genomics, Zayed Centre for Research, University College London, London, United Kingdom.
  • 11 Chemical Biology & Drug Discovery Lab, School of Pharmaceutical Chemistry, Faculty of Medicine and Science, San Sebastián University, Providencia, Santiago, Chile.
PMID: 35138268 DOI: 10.1172/jci.insight.154671
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 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.

Keywords

Endocrinology; Genetic diseases; Genetics; Molecular genetics; Reproductive biochemistry.

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