Wang Chunlin, Chen Hong, Chen Qingqing, Qu Yangbin, Yuan Ke, Liang Li, Yan Qingfeng
Department of Pediatrics, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Department of Endocrinology, Fuzhou Children's Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Biol Res. 2025 Jan 7;58(1):1. doi: 10.1186/s40659-024-00583-1.
Karyotype 46, XY female disorders of sex development (46, XY female DSD) are congenital conditions due to irregular gonadal development or androgen synthesis or function issues. Genes significantly influence DSD; however, the underlying mechanisms remain unclear. This study identified a Chinese family with 46, XY female DSD due to the CUL4B gene.
The proband medical history and pedigree were investigated. Whole-exome sequencing was performed to analyze different variations. Transiently transfected testicular teratoma (NT2/D1), KGN ovarian cells with either mutant or wild-type CUL4B gene, and knock-in Cul4b mouse models were confirmed. The expression levels of sex-related genes were analyzed.
A 9.5-year-old girl was diagnosed with 46, XY DSD. A hemizygous variant c.838 T > A of the CUL4B gene was detected. The mRNA and protein levels of WNT4 and FOXL2 genes were higher than those in the wild-type group; however, CTNNB1, SOX9, and DMRT1 were lower in the wild-type group in NT2/D1 cells. In KGN ovarian cells of the mutant group, the mRNA and protein levels for WNT4 and CTNNB1 were elevated. Damaged testicular vasculature and underdeveloped seminal vesicles were observed in Cul4b mice.
A missense CUL4B variant c.838 T > A associated with 46, XY female DSD was identified, and may activate the Wnt4/β-catenin pathway. Our findings provide novel insights into the molecular mechanisms of 46, XY female DSD.
核型为46, XY的女性性发育障碍（46, XY女性DSD）是由于性腺发育异常或雄激素合成或功能问题导致的先天性疾病。基因对DSD有显著影响；然而，其潜在机制仍不清楚。本研究鉴定了一个因CUL4B基因导致46, XY女性DSD的中国家系。
对先证者的病史和家系进行调查。进行全外显子测序以分析不同变异。对转染了突变型或野生型CUL4B基因的睾丸畸胎瘤（NT2/D1）、KGN卵巢细胞以及敲入Cul4b基因的小鼠模型进行了验证。分析了性别相关基因的表达水平。
一名9.5岁女孩被诊断为46, XY DSD。检测到CUL4B基因的一个半合子变异c.838 T＞A。在NT2/D1细胞中，WNT4和FOXL2基因的mRNA和蛋白水平高于野生型组；然而，CTNNB1、SOX9和DMRT1在野生型组中较低。在突变组的KGN卵巢细胞中，WNT4和CTNNB1的mRNA和蛋白水平升高。在Cul4b小鼠中观察到睾丸血管受损和精囊发育不全。
鉴定出一个与46, XY女性DSD相关的错义CUL4B变异c.838 T＞A，其可能激活Wnt4/β-连环蛋白通路。我们的研究结果为46, XY女性DSD的分子机制提供了新的见解。
