4.4 Article

Novel mutations in ZP2 and ZP3 cause female infertility in three patients

Journal

JOURNAL OF ASSISTED REPRODUCTION AND GENETICS
Volume 39, Issue 5, Pages 1205-1215

Publisher

SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10815-022-02466-4

Keywords

ZP2; ZP3; Mutation; Abnormal zona pellucida; Empty follicle syndrome

Funding

  1. National Natural Science Foundation of China [81000079, 81170165, 81870959]
  2. Program for HUST Academic Frontier Youth Team [2016QYTD02]
  3. Fundamental Research Funds for the Central Universities [HUST: 2019JYCXJJ035]

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The aim of this study was to identify disease-causing mutations in three infertile female patients diagnosed with abnormal zona pellucida and empty follicle syndrome. The study found three novel mutations in the ZP2 and ZP3 genes, expanding the spectrum of ZP gene mutations and phenotypes, which is beneficial for the genetic diagnosis of infertility in females.
Purpose The aim of this study was to identify the disease-causing mutations found in three infertile female patients who were diagnosed with abnormal zona pellucida (ZP) and empty follicle syndrome (EFS). Methods We performed whole-exome sequencing and Sanger sequencing to identify and verify the disease-causing mutations. Additionally, we performed Western blotting and mini-gene splicing assay to assess the effects of the mutations. Results We identified two novel compound heterozygous mutations in the ZP2 gene, a patient with an abnormal ZP carrying a novel compound heterozygous mutation (c.1695-2A>G and c.1831G>T, p.V611F) and a patient with EFS carrying a novel compound heterozygous mutation (c.1695-2A>G and c.1924 C>T, p.R642*). Furthermore, we identified a patient with typical abnormal ZP carrying a novel heterozygous mutation (c.400G>T, p.A134S) in the ZP3 gene. The splice site mutation (c.1695-2A>G) can cause abnormal pre-mRNA splicing that inserts an extra sequence of 61 bp in the mRNA of ZP2, and the missense mutation (c.1831G>T) can cause a decrease of ZP2 protein in HEK293 cells. Conclusion We identified three novel mutations in the ZP2 gene and the ZP3 gene in three Chinese female patients with infertility. Our study expands the spectrum of ZP gene mutations and phenotypes and thus is beneficial in the genetic diagnosis of infertility in females.

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