Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.
Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland.
Int J Mol Sci. 2024 Sep 20;25(18):10109. doi: 10.3390/ijms251810109.
Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. /SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts with numerous partners. Here, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual carrying an ACMG-categorized 'pathogenic' /SF-1 variant in comparison to the healthy carrier father. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in and associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the and gene promoters were found. Transactivation studies showed that wild-type /SF-1 regulates and gene expression, while the /SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate gene transcription; however, the NR1H2 variant showed normal activity. This study expands the /SF-1 network of interacting partners, while not solving the exact interplay of different variants that might be involved in revealing the observed DSD phenotype. It also illustrates that understanding complex genetics in DSDs is challenging.
类固醇生成因子 1（SF-1）是一种核受体，可调节类固醇生成和生殖发育。/SF-1 变体与性别发育障碍（DSD）个体的广泛表型相关。有人提出寡基因遗传是一种解释。SF-1 与许多伴侣相互作用。在这里，我们研究了在携带 ACMG 分类为“致病性”/SF-1 变体的 46,XY 严重发育不全个体中与健康携带者父亲相比鉴定出的一组基因变体。通过全外显子组测序揭示候选基因，并通过不同的计算工具预测其致病性。我们发现与类固醇生成、性发育和生殖相关的 和 基因中的变体。鉴定出的变体在细胞模型中进行了测试。在 和 基因启动子中发现了新的 SF-1 和 NR1H2 结合位点。转激活研究表明，野生型/SF-1 调节 和 基因表达，而 /SF-1 变体的转录活性降低。发现 NR1H2 调节 基因转录；然而，NR1H2 变体表现出正常的活性。这项研究扩展了/SF-1 的相互作用伙伴网络，而没有解决可能涉及揭示观察到的 DSD 表型的不同变体的确切相互作用。它还表明，理解 DSD 中的复杂遗传是具有挑战性的。
