Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility.

Abstract

Fertilization is a fundamental process of development and is a prerequisite for successful human reproduction. In mice, although several receptor proteins have been shown to play important roles in the process of fertilization, only three genes have been shown to cause fertilization failure and infertility when deleted in vivo. In clinical practice, some infertility case subjects suffer from recurrent failure of in vitro fertilization and intracytoplasmic sperm injection attempts due to fertilization failure, but the genetic basis of fertilization failure in humans remains largely unknown. Wee2 is a key oocyte-specific kinase involved in the control of meiotic arrest in mice, but WEE2 has not been associated with any diseases in humans. In this study, we identified homozygous mutations in WEE2 that are responsible for fertilization failure in humans. All four independent affected individuals had homozygous loss-of-function missense mutations or homozygous frameshift protein-truncating mutations, and the phenotype of fertilization failure was shown to follow a Mendelian recessive inheritance pattern. All four mutations significantly decreased the amount of WEE2 protein in vitro and in affected individuals' oocytes in vivo, and they all led to abnormal serine phosphorylation of WEE2 and reduced tyrosine 15 phosphorylation of Cdc2 in vitro. In addition, injection of WEE2 cRNA into affected individuals' oocytes rescued the fertilization failure phenotype and led to the formation of blastocysts in vitro. This work presents a novel gene responsible for human fertilization failure and has implications for future therapeutic treatments for infertility cases.

• Authors: Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang Chen, Ling Wu, Qifeng Lyu, Yonglun Fu, Zheng Yan, Xiaoyan Mao, Yao Xu, Jian Mu, Qiaoli Li, Li Jin, Lin He, Lei Wang
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 102 Issue 4 Pg. 649-657 (04 05 2018) ISSN: 1537-6605 [Electronic] United States
• PMID: 29606300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Mutant Proteins
• RNA, Complementary
• Wee2 protein, human
• Protein-Tyrosine Kinases
• CDC2 Protein Kinase
• Cdk1 protein, mouse

Topics

• Adult
• Amino Acid Sequence
• Base Sequence
• CDC2 Protein Kinase (metabolism)
• Cell Cycle Proteins (chemistry, genetics)
• Family
• Female
• Fertilization (genetics)
• HeLa Cells
• Homozygote
• Humans
• Infertility, Female (genetics)
• Male
• Mutant Proteins (metabolism)
• Mutation (genetics)
• Oocytes (metabolism)
• Pedigree
• Phenotype
• Phosphorylation
• Protein-Tyrosine Kinases (chemistry, genetics)
• RNA, Complementary (administration & dosage)
• Sperm Injections, Intracytoplasmic
• Zygote (metabolism)