Can Non-Coding NR5A1 Gene Variants Explain Phenotypes of Disorders of Sex Development?

IF 2.4 4区医学 Q2 DEVELOPMENTAL BIOLOGY Sexual Development Pub Date : 2022-01-01 DOI:10.1159/000524956

Helena Fabbri-Scallet, Ralf Werner, Mara S Guaragna, Juliana G R de Andrade, Andrea T Maciel-Guerra, Nadine C Hornig, Olaf Hiort, Gil Guerra-Júnior, Maricilda P de Mello

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引用次数: 3

Abstract

Introduction: 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).

Methods: The molecular study involved Sanger sequencing, in vitro assays, and whole exome sequencing (WES).

Results: 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.

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非编码NR5A1基因变异能否解释性发育障碍的表型?

简介:NR5A1是一种重要的转录因子，可调控多种涉及生殖和内分泌功能的靶基因。该基因的致病性变异导致了广泛的性发育障碍/差异(DSD)。方法:分子研究包括Sanger测序、体外检测和全外显子组测序(WES)。结果:3例46,xy DSD患者在NR5A1非编码区鉴定出4个变异。体外分析表明，启动子活性在所有情况下都受到影响。WES发现SRA1、WWOX和WDR11基因变异。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是复杂的，并且对其与DSD的关系知之甚少。然而，基于与辅助因子相互作用的重要区域，促进适当的性发育，以及我们的体外结果，可以说对基因表达的影响是可以预期的，这可能与我们患者中呈现的DSD病理生理有关。考虑到在筛选众所周知的DSD相关基因后仍然难以找到的病例数量，我们强调对NR5A1非编码区进行仔细的分子分析的重要性，NR5A1非编码区通常被忽视，可能解释一些特发性DSD病例。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Sexual Development 生物-发育生物学

CiteScore

4.00

自引率

4.30%

发文量

审稿时长

>12 weeks

期刊介绍： Recent discoveries in experimental and clinical research have led to impressive advances in our knowledge of the genetic and environmental mechanisms governing sex determination and differentiation, their evolution as well as the mutations or endocrine and metabolic abnormalities that interfere with normal gonadal development. ‘Sexual Development’ provides a unique forum for this rapidly expanding field. Its broad scope covers all aspects of genetics, molecular biology, embryology, endocrinology, evolution and pathology of sex determination and differentiation in humans and animals. It publishes high-quality original research manuscripts, review articles, short reports, case reports and commentaries. An internationally renowned and multidisciplinary editorial team of three chief editors, ten prominent scientists serving as section editors, and a distinguished panel of editorial board members ensures fast and author-friendly editorial processing and peer reviewing.