ESPE Abstracts

Background: 46, XY female disorders of sex development (46, XY female DSD) are congenital conditions caused by abnormal gonadal development or in androgen synthesis or action. Genes play an important role in DSD, but mechanisms are not clear. This study identified a Chinese family with the 46, XY female DSD caused by the CUL4B gene.

Method: s: The proband medical history and pedigree were investigated. Variants analysis was conducted using whole-exome sequencing. 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.

Results: A 9.5-year-old girl was diagnosed with 46, XY female DSD. A hemizygous variant c.838T>A of the CUL4B gene was detected. The mRNA and protein expression of CUL4B showed no significant difference between the wild-type and mutant groups in NT2/D1 or KGN ovarian cells. The mRNA and protein levels of WNT4 and FOXL2 genes were higher than those in the wild-type group, but CTNNB1, SOX9, and DMRT1 were lower in the wild-type group in NT2/D1 cells. The mRNA and protein levels of WNT4 and CTNNB1 in KGN ovarian cells of the mutant group were higher. Damaged testicular vasculature and underdeveloped seminal vesicles were observed in Cul4bL337M mice.

Conclusions: A missense CUL4B variant c.838T>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.