PDF(Pubmed)
Abstract：
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.
摘要：
NR2F2编码COUP-TFII,小鼠胎儿睾丸和卵巢类固醇生成谱系发育所需的孤儿核受体。人NR2F2中的致病变异与46,XX个体的睾丸形成有关,然而,COUP-TFII在人类睾丸中的功能未知。我们报告了NR2F2中的从头杂合变体（c.737G>A，p.Arg246His）在一个46，XY男性化不足的男孩中，患有原发性性腺功能减退。变种,位于配体结合域内，预计会有很大的破坏性。体外研究表明突变不影响蛋白质的稳定性或亚细胞定位。NR5A1，一种相关的核受体，是性腺形成和功能的关键因素，已知与COUP-TFII物理相互作用以调节基因表达。突变蛋白不影响与NR5A1的物理相互作用。然而,体外实验表明，突变蛋白对NR5A1介导的LHB和INSL3启动子激活的抑制作用显着丧失。数据支持COUP-TFII在人睾丸形成中的作用。尽管已知相互拮抗的基因集可调节睾丸和卵巢途径，我们扩展了基因列表，与NR5A1和WT1一起，与46，XX和46，XYDSD相关联。
