Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency
Sinéad M. McGlacken-Byrne, … , Gerard S. Conway, John C. Achermann
Sinéad M. McGlacken-Byrne, … , Gerard S. Conway, John C. Achermann
Published February 8, 2022
Citation Information: JCI Insight. 2022;7(5):e154671. https://doi.org/10.1172/jci.insight.154671.
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Research Article Endocrinology Genetics

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 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.

Authors

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, GOSgene, 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

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Figure 1

YTHDC2 variants identified.

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YTHDC2 variants identified. (A) Pedigrees of kindred with YTHDC2 variant...
(A) Pedigrees of kindred with YTHDC2 variants (upper panel: p.P856R, lower panel: p.E377*). Solid symbols indicate affected family members. Genotype is indicated underneath tested family members. (B) Domains of the human YTHDC2 protein. Domains include an R3H domain; 2 RecA-like domains, RecA1: ATP-binding DEAD-like helicase domain (DExDc) and RecA2: helicase superfamily C-terminal domain (HELICc); 2 ankyrin repeats (506–535 and 539–568) comprising the ankyrin domain (ANK); a helicase-associated domain (HA2), an oligonucleotide/oligosaccharide-binding fold domain (OB-fold), and a YTH (YT521-B homology) m6A-dependent RNA binding domain (YTH). The DExDc, ankyrin repeats, and HELICc domains make up the helicase core of this protein. Domain positions (in amino acids) are annotated below the schematic. The position of the 2 pathogenic variants (p.E377*; p.P856R); the ketu mouse mutation (mouse: p.H327R; human: p.H312R) (Jain et al. 2017, ref. 26); and another Ythdc2–/– knockout mouse (deletion of 50 amino acids within exon 7) (Wojtas et al. 2017, ref. 27) are indicated. (C) Amino acid conservancy in the region of YTHDC2 surrounding codon 856. Yellow asterisks represent complete conservation among the species shown. (D) The m6A methyltransferase complex. The m6A modification on mRNA is mediated by “writers” and demethylases (“erasers”). “Readers” recognize the m6A modification and allow execution of its functions. One key reader is YTHDC2, with its known cofactors MEIOC and XRN.