Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, the Ministry of Science and Technology, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
J Assist Reprod Genet. 2021 May;38(5):1239-1245. doi: 10.1007/s10815-021-02107-2. Epub 2021 Feb 18.
We aimed to identify pathogenic variants in two infertile sisters in a family with a thin zona pellucida (ZP) phenotype.
Whole-exome sequencing was performed in the two affected sisters, and Sanger sequencing was used to confirm the identified variants. The effects of the identified variant were further investigated in mouse oocytes and Chinese hamster ovary (CHO) cells.
We identified a novel homozygous frameshift variant in ZP2 (c.1235_1236del, p.Q412Rfs*17) in the two affected individuals. Immunoblotting demonstrated that the variant produced a truncated ZP2 protein that was expressed at low levels in CHO cells. Immunofluorescence in mouse oocytes confirmed the decreased protein level of mutant ZP2, although the subcellular localization was not affected. In addition, immunoprecipitation showed that the pathogenic variant reduced the interaction between ZP2 and ZP3.
This study identified a novel pathogenic variant in ZP2 that produces a truncated ZP2 protein. The variant might disrupt the assembly of ZP2-ZP3 dimers, thus resulting in a thin ZP and female infertility.
我们旨在鉴定一个薄透明带（ZP）表型家系中两名不孕姐妹的致病性变异。
对两名受影响的姐妹进行全外显子组测序，并通过 Sanger 测序对鉴定的变异进行确认。进一步在小鼠卵母细胞和中国仓鼠卵巢（CHO）细胞中研究鉴定变异的影响。
我们在两名受影响个体中鉴定出 ZP2 中的一个新的纯合移码变异（c.1235_1236del，p.Q412Rfs*17）。免疫印迹表明该变异产生了一个截断的 ZP2 蛋白，在 CHO 细胞中低水平表达。在小鼠卵母细胞中的免疫荧光证实了突变 ZP2 的蛋白水平降低，尽管亚细胞定位未受影响。此外，免疫沉淀表明该致病性变异降低了 ZP2 和 ZP3 之间的相互作用。
本研究鉴定出 ZP2 中的一个新型致病性变异，该变异产生了一个截断的 ZP2 蛋白。该变异可能破坏 ZP2-ZP3 二聚体的组装，从而导致薄透明带和女性不孕。
