Functional and clinical insights into nuclear receptor variants for advancing precision diagnostics in male infertility.

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
EBioMedicine Pub Date : 2025-09-01 Epub Date: 2025-08-28 DOI:10.1016/j.ebiom.2025.105899
Avinash S Gaikwad, Margot J Wyrwoll, Sophie A Koser, Jana Emich, Johanna Kuß, Mariya Aravina, Claudia Krallmann, Jörg Gromoll, Sabine Kliesch, Sandra Laurentino, Birgit Stallmeyer, Corinna Friedrich, Frank Tüttelmann
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引用次数: 0

Abstract

Background: Nuclear receptors, including steroidogenic factor 1 (NR5A1/SF1) and the androgen receptor (AR), are transcription factors regulating physiological processes, e.g., reproduction. Pathogenic variants in these receptors are associated with a broad spectrum of phenotypes, ranging from differences in sexual development to isolated male infertility. However, standardised methods to classify variants of uncertain significance (VUS) in these genes are lacking, complicating diagnosis and individualised treatment.

Methods: We queried rare NR5A1 and AR variants in exome/genome sequencing data of 2127 infertile men. Pathogenicity assessment included thorough clinical phenotyping, familial segregation, in silico pathogenicity prediction combining traditional and machine-learning tools, and functional evaluation of the variants using in vitro assays.

Findings: We identified a total of seven heterozygous NR5A1 variants in 10 infertile men and 22 hemizygous AR variants in 31 infertile men with severe oligo-/azoospermia. Of these, three SF1 and seven AR variants displayed significantly reduced transcriptional activity. This study led to the reclassification of one NR5A1 variant and ten AR variants, including three AR variants that were reclassified from VUS to (likely) pathogenic. Combined phenotype, in silico, and in vitro data led to 60% of all variants (17 out of 29) being classified as (likely) pathogenic per ACMG guidelines, providing insights into the phenotypic features and spermatogenic impairment in affected men.

Interpretation: This study highlights the importance of combining clinical and experimental data for the assessment of VUS in nuclear receptors to reliably classify pathogenicity and to improve patient diagnosis and care.

Funding: This study was carried out within the frame of the Deutsche Forschungsgemeinschaft (DFG)-sponsored Clinical Research Unit 'Male Germ Cells' (CRU326, project 329621271, to F.T., C.F., S.L., and J.G.) and the German Federal Ministry of Education and Research (BMBF)-sponsored Junior Scientist Research Centre 'ReproTrack.MS' (grant 01GR2303, to F.T. and S.K.), and was supported by the Medical Faculty Münster via an Innovative Medical Research (IMF) grant (GA-122104, to A.S.G.) and the Clinician Scientist programme CareerS (to S.A.K.).

功能性和临床洞察核受体变异推进精确诊断在男性不育。
背景:核受体,包括甾体生成因子1 (NR5A1/SF1)和雄激素受体(AR),是调节生殖等生理过程的转录因子。这些受体的致病变异与广泛的表型相关,从性发育的差异到孤立的男性不育。然而,缺乏对这些基因中不确定意义变异(VUS)进行分类的标准化方法,使诊断和个体化治疗复杂化。方法:对2127例不育男性外显子组/基因组测序数据中罕见的NR5A1和AR变异进行查询。致病性评估包括全面的临床表型,家族分离,结合传统和机器学习工具的计算机致病性预测,以及使用体外试验对变异进行功能评估。结果:我们在10名患有严重少精/无精症的不育男性中发现了7个杂合子NR5A1变异,在31名患有严重少精/无精症的不育男性中发现了22个半合子AR变异。其中,3个SF1和7个AR变异的转录活性显著降低。该研究导致1个NR5A1变异和10个AR变异重新分类,包括3个AR变异从VUS重新分类为(可能)致病。根据ACMG指南,综合表型,计算机和体外数据导致60%的变异(29个中的17个)被归类为(可能的)致病性,为受影响男性的表型特征和生精损伤提供了见解。解释:本研究强调了结合临床和实验数据评估核受体VUS的重要性,以可靠地分类致病性,提高患者的诊断和护理。资助:本研究是在德国研究基金会(DFG)资助的临床研究单位“男性生殖细胞”(CRU326,项目329621271,给F.T, c.f., s.l.和J.G.)和德国联邦教育和研究部(BMBF)资助的青年科学家研究中心“retrack”的框架内进行的。MS'(资助01GR2303,给F.T.和S.K.),并得到了医学院国家科学技术研究院通过创新医学研究(IMF)资助(GA-122104,给A.S.G.)和临床科学家计划职业(给S.A.K.)的支持。
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
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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