Evidence for NR2F2/COUP-TFII involvement in human testis development
Wankanit, S.; Zidoune, H.; Bignon-Topalovic, J.; Schlick, L.; Houzelstein, D.; Fusee, L.; Boukri, A.; Nouri, N.; McElreavey, K.; Bashamboo, A.; Elzaiat, M.
Show abstract
NR2F2 encodes COUP-TFII, an orphan nuclear receptor involved in mammalian gonadogenesis. COUP-TFII is expressed in the interstitial/stromal compartment of both fetal testes and ovaries, where it is required for developing steroidogenic lineages. Pathogenic variants in human NR2F2 are linked to testis formation in 46,XX individuals (46,XX disorders of sex development, 46,XX DSD). Such findings propose a regulatory role of COUP-TFII in the developing ovary, whereas its function in testis remains unknown. We evaluate the effect of a de novo heterozygous, predicted damaging, missense variant in NR2F2 (p.Arg246His) in a 46,XY under-masculinized boy. In-vitro assays show that the mutant protein significantly loses the inhibitory effect on NR5A1-mediated activation of both the LHB and INSL3 promoters. The data support the pathogenicity of the p.Arg246His variant in 46,XY DSD and a role for NR2F2 in human testis formation. In addition to NR5A1 and WT1, NR2F2 variants are thus associated with both 46,XX and 46,XY DSD. This expands the list of genes that function in both male and female sex development, which is originally thought to be regulated by two entirely different sets of genes.
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