Center for Molecular Biology and Genetic Engineering - CBMEG, State University of Campinas, São Paulo, Brazil.
Interdisciplinary Group for the Study of Sex Determination and Differentiation - GIEDDS, State University of Campinas, São Paulo, Brazil.
Sex Dev. 2022;16(4):252-260. doi: 10.1159/000524956. Epub 2022 Jun 28.
NR5A1 is an essential transcription factor that regulates several target genes involved in reproduction and endocrine function. Pathogenic variants in this gene are responsible for a wide spectrum of disorders/differences of sex development (DSD).
The molecular study involved Sanger sequencing, in vitro assays, and whole exome sequencing (WES).
Four variants were identified within the NR5A1 non-coding region in 3 patients with 46,XY DSD. In vitro analyses showed that promoter activity was affected in all cases. WES revealed variants in SRA1, WWOX, and WDR11 genes.
DISCUSSION/CONCLUSION: Evaluation of clinical and phenotypic significance of variants located in a non-coding region of a gene can be complex, and little is known regarding their association with DSD. Nevertheless, based on the important region for interaction with cofactors essential to promote appropriated sex development and on our in vitro results, it is feasible to say that an impact on gene expression can be expected and that this may be correlated with the DSD pathophysiology presented in our patients. Considering the number of cases that remain elusive after screening for the well-known DSD related genes, we emphasize the importance of a careful molecular analysis of NR5A1 non-coding region which is commonly neglected and might explain some idiopathic DSD cases.
NR5A1 是一种重要的转录因子，可调节参与生殖和内分泌功能的多个靶基因。该基因的致病性变异可导致广泛的性发育障碍/差异（DSD）。
分子研究包括 Sanger 测序、体外检测和全外显子组测序（WES）。
在 3 名 46,XY DSD 患者的 NR5A1 非编码区发现了 4 种变体。体外分析表明所有病例的启动子活性均受到影响。WES 显示 SRA1、WWOX 和 WDR11 基因的变体。
讨论/结论：评估位于基因非编码区的变异的临床和表型意义可能很复杂，并且对于它们与 DSD 的相关性知之甚少。然而，基于与促进适当性别发育的必需辅助因子相互作用的重要区域以及我们的体外结果，可以说预计会对基因表达产生影响，并且这可能与我们患者中存在的 DSD 病理生理学相关。考虑到在筛选众所周知的 DSD 相关基因后仍有许多病例难以解释，我们强调对通常被忽视且可能解释一些特发性 DSD 病例的 NR5A1 非编码区进行仔细分子分析的重要性。
