Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency.
Endocrinology
Genetic diseases
Genetics
Molecular genetics
Reproductive biochemistry
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
08 03 2022
08 03 2022
Historique:
received:
08
09
2021
accepted:
26
01
2022
pubmed:
10
2
2022
medline:
12
4
2022
entrez:
9
2
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35138268
pii: 154671
doi: 10.1172/jci.insight.154671
pmc: PMC8983136
doi:
pii:
Substances chimiques
N-methyladenosine
CLE6G00625
RNA Helicases
EC 3.6.4.13
YTHDC2 protein, human
EC 3.6.4.13
Adenosine
K72T3FS567
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 216362/Z/19/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 209328/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R006237/1
Pays : United Kingdom
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