J Clin Invest. 2014 May;124(5):2071-5. doi: 10.1172/JCI73186. Epub 2014 Apr 8.
The transcription factor steroidogenic factor 1 (SF-1; also known as NR5A1) is a crucial mediator of both steroidogenic and nonsteroidogenic tissue differentiation. Mutations within SF1 underlie different disorders of sexual development (DSD), including sex reversal, spermatogenic failure, ovarian insufficiency, and adrenocortical deficiency. Here, we identified a recessive mutation within SF1 that resulted in a substitution of arginine to glutamine at codon 103 (R103Q) in a child with both severe 46,XY-DSD and asplenia. The R103Q mutation decreased SF-1 transactivation of TLX1, a transcription factor that has been shown to be essential for murine spleen development. Additionally, the SF1 R103Q mutation impaired activation of steroidogenic genes, without affecting synergistic SF-1 and sex-determining region Y (SRY) coactivation of the testis development gene SOX9. Together, our data provide evidence that SF-1 is required for spleen development in humans via transactivation of TLX1 and that mutations that only impair steroidogenesis, without altering the SF1/SRY transactivation of SOX9, can lead to 46,XY-DSD.
转录因子类固醇生成因子 1（SF-1；也称为 NR5A1）是类固醇生成和非类固醇生成组织分化的关键介质。SF1 内的突变是不同性发育障碍（DSD）的基础，包括性反转、精子发生衰竭、卵巢功能不全和肾上腺皮质功能不足。在这里，我们在一名患有严重 46,XY-DSD 和脾缺失的儿童中发现了 SF1 内的隐性突变，导致密码子 103 处的精氨酸替换为谷氨酰胺（R103Q）。R103Q 突变降低了 TLX1 的 SF-1 转录激活，TLX1 已被证明对小鼠脾脏发育至关重要。此外，SF1 R103Q 突变损害了类固醇生成基因的激活，而不影响睾丸发育基因 SOX9 的协同 SF-1 和性别决定区 Y（SRY）激活。总之，我们的数据提供了证据，表明 SF-1 通过 TLX1 的转录激活对于人类脾脏发育是必需的，并且仅损害类固醇生成而不改变 SF1/SRY 对 SOX9 的转录激活的突变可导致 46,XY-DSD。
