Evidence for NR2F2/COUP-TFII involvement in human testis development.
46,XY disorders/differences of sex development/differentiation (DSD)
COUP-TFII
NR2F2
Sex determination
Under-virilization
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
01 Aug 2024
01 Aug 2024
Historique:
received:
27
03
2024
accepted:
29
07
2024
medline:
2
8
2024
pubmed:
2
8
2024
entrez:
1
8
2024
Statut:
epublish
Résumé
NR2F2 encodes COUP-TFII, an orphan nuclear receptor required for the development of the steroidogenic lineages of the murine fetal testes and ovaries. Pathogenic variants in human NR2F2 are associated with testis formation in 46,XX individuals, however, the function of COUP-TFII in the human testis is unknown. We report a de novo heterozygous variant in NR2F2 (c.737G > A, p.Arg246His) in a 46,XY under-masculinized boy with primary hypogonadism. The variant, located within the ligand-binding domain, is predicted to be highly damaging. In vitro studies indicated that the mutation does not impact the stability or subcellular localization of the protein. NR5A1, a related nuclear receptor that is a key factor in gonad formation and function, is known to physically interact with COUP-TFII to regulate gene expression. The mutant protein did not affect the physical interaction with NR5A1. However, in-vitro assays demonstrated that the mutant protein significantly loses the inhibitory effect on NR5A1-mediated activation of both the LHB and INSL3 promoters. The data support a role for COUP-TFII in human testis formation. Although mutually antagonistic sets of genes are known to regulate testis and ovarian pathways, we extend the list of genes, that together with NR5A1 and WT1, are associated with both 46,XX and 46,XY DSD.
Identifiants
pubmed: 39090159
doi: 10.1038/s41598-024-68860-3
pii: 10.1038/s41598-024-68860-3
doi:
Substances chimiques
COUP Transcription Factor II
0
NR2F2 protein, human
0
Steroidogenic Factor 1
0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
17869Subventions
Organisme : Agence Nationale de la Recherche
ID : ANR-10-LABX-73 REVIVE
Organisme : Agence Nationale de la Recherche
ID : ANR-19-CE14-0022
Informations de copyright
© 2024. The Author(s).
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