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
  • 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.