Yiming Sun1, Yang Zeng2, Hua Chen3, Zhou Zhou2, Jing Fu3, Qing Sang2, Lei Wang2, Xiaoxi Sun3, Biaobang Chen4, Congjian Xu5. 1. Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China. 2. 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. 3. Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China. 4. NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, 200032, China. chenbiaobang@163.com. 5. Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China. xucj@hotmail.com.
Abstract
PURPOSE: We aimed to identify pathogenic variants in two infertile sisters in a family with a thin zona pellucida (ZP) phenotype. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
PURPOSE: We aimed to identify pathogenic variants in two infertile sisters in a family with a thin zona pellucida (ZP) phenotype. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Entities:
Keywords:
Female infertility; Novel variant; ZP2; Zona pellucida