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, 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
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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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 4

Structural modeling and simulation of human YTHDC2.

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Structural modeling and simulation of human YTHDC2. (A) The HA2 domain i...
(A) The HA2 domain is shown in green and codon P856 is indicated by an arrow. The RNA-binding domain is shown with the bound RNA in orange. (B) P856R can establish strong hydrogen bond interactions with surrounding residues (D855,T859, Q905, Q908, R937, R959, N967), which is predicted to increase stability and to reduce flexibility of the P856R protein. (C) The radius of gyration (RoG) indicates that P856R mutant protein is more compact than WT protein (left panel), and there is an increased number of protein-RNA hydrogen bonds in the P856R protein compared with WT (right panel), suggesting the P856R protein to be more stable and less flexible than WT. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. ****P < 0.0001, unpaired t test. (D) Root-mean square deviation (RMSD) of alpha carbons at the protein and nucleic acid (NA) level for both WT and P856R mutant YTHDC2. Global movement is lower in the P856R mutant protein compared with WT. (E) Replacement of proline at position 856 with arginine may also alter the electrostatic charge of YTHDC2.