Wankanit Somboon, Zidoune Housna, Bignon-Topalovic Joëlle, Schlick Laurène, Houzelstein Denis, Fusée Leila, Boukri Asma, Nouri Nassim, McElreavey Ken, Bashamboo Anu, Elzaiat Maëva
Human Developmental Genetics Unit, CNRS UMR 3738, Institut Pasteur, 75015, Paris, France.
Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
Sci Rep. 2024 Aug 1;14(1):17869. doi: 10.1038/s41598-024-68860-3.
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.
NR2F2编码COUP-TFII，这是一种孤儿核受体，对于小鼠胎儿睾丸和卵巢的类固醇生成谱系的发育是必需的。人类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尚不清楚。我们报告了一名患有原发性性腺功能减退的46,XY男性化不足男孩中NR2F2的一个新生杂合变异（c.737G＞A，p.Arg246His）。该变异位于配体结合域内，预计具有高度危害性。体外研究表明，该突变不影响蛋白质的稳定性或亚细胞定位。NR5A1是一种相关的核受体，是性腺形成和功能的关键因素，已知它与COUP-TFII发生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，体外试验表明，突变蛋白显著丧失了对NR5A1介导的促黄体生成素（LHB）和胰岛素样肽3（INSL3）启动子激活的抑制作用。这些数据支持COUP-TFII在人类睾丸形成中的作用。虽然已知相互拮抗的基因集调节睾丸和卵巢途径，但我们扩展了与46,XX和46,XY性发育障碍（DSD）相关的基因列表，这些基因与NR5A1和WT1一起。
