Evidence forNR2F2/COUP-TFII involvement in human testis development

Abstract

AbstractNR2F2encodes 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 humanNR2F2are linked to testis formation in 46,XX individuals (46,XXdisorders ofsexdevelopment, 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 ade novoheterozygous, predicted damaging, missense variant inNR2F2(p.Arg246His) in a 46,XY under-masculinized boy.In-vitroassays show that the mutant protein significantly loses the inhibitory effect on NR5A1-mediated activation of both theLHBandINSL3promoters. The data support the pathogenicity of the p.Arg246His variant in 46,XY DSD and a role forNR2F2in human testis formation. In addition toNR5A1andWT1,NR2F2variants 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.