Novel biallelic loss-of-function variants in ZP1 identified in an infertile female with empty follicle syndrome
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GENETICS
Novel biallelic loss-of-function variants in ZP1 identified in an infertile female with empty follicle syndrome Mohan Liu 1,2 & Ying Shen 2 & Xueguang Zhang 2 & Xiang Wang 2 & Dan Li 3 & Yan Wang 4 Received: 7 January 2020 / Accepted: 7 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Empty follicle syndrome (EFS) refers to the inability to obtain mature oocytes after appropriate ovarian stimulation during the process of in vitro fertilization (IVF). However, the specific cause and mechanism of action underlying EFS remain to be further explored. Herein we aimed to investigate the clinical and genetic characteristics of EFS. Methods After data were collected in an infertile family, we performed whole-exome sequencing (WES) on the patient and confirmed the pathogenic mutations through Sanger sequencing. Western immunoblotting, immunofluorescence staining, and minigene assay were further used to investigate the negative effects of these mutations. Results Absence of oocytes was observed over 2 cycles of IVF in the patient, and we evaluated the novel compound heterozygous mutations c.2T>A (p. M1K) and c.1112+1G>T of the zona pellucida glycoprotein 1 gene (ZP1, MIM# 195000) by WES. For the family under study, EFS was classified as an autosomal recessive inheritance pattern. The results of western blotting and immunofluorescence staining analyses confirmed that the missense mutation of c.2T>A [p. M1K] resulted in almost missing protein production. Additionally, using a minigene assay, we demonstrated the deleterious effect on the ZP1 gene of the splice site mutation c.1112+1G>T, which caused truncation of ZP1 protein. Conclusions The compound heterozygous mutations of ZP1 gene identified in this study by genetic and functional experiments constituted a novel genetic cause of EFS, and further study will expand its use in the clinical and molecular diagnoses of EFS. Keywords Empty follicle syndrome . ZP1 . Gene mutation . WES
Introduction Mohan Liu and Ying Shen contributed equally to this work. * Yan Wang [email protected] 1
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China
2
Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China
3
Clinical Laboratory, The Fourth People’s Hospital of Zigong, Zigong 643000, China
4
Reproduction Medical Center of West China Second University Hospital, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China
Empty follicle syndrome (EFS) is a phenomenon whereby follicles develop well before ovulation in natural or inducedovulation cycles; even though the size and number of follicles and the concentrations
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