New biallelic mutations in WEE2: expanding the spectrum of mutations that cause fertilization failure or poor fertilization

Novel mutations in the known causative gene WEE2 were identified by whole-exome sequencing in 5 of 24 Chinese women with fertilization failure or poor fertilization.

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Volume 111, Issue 3, Pages 510–518

Authors:

Jing Dai, M.S., Wei Zheng, Ph.D., Can Dai, Ph.D., Jing Guo, Ph.D., Changfu Lu, Ph.D., Fei Gong, M.D., Ph.D., Yan Li, M.D., Qinwei Zhou, B.S., Guangxiu Lu, M.D., Ge Lin, M.D., Ph.D.

Abstract:

Objective

To investigate the genetic cause of fertilization failure or poor fertilization.

Design

Genetic analysis.

Setting

University-affiliated center.

Patient(s)

Twenty-four Chinese women who underwent assisted reproductive technology (ART) and had repeated fertilization failure or poor fertilization.

Intervention(s)

None.

Main Outcome Measure(s)

Twenty-four affected patients were subjected to whole-exome sequencing and candidate mutations were validated by Sanger sequencing. Single-cell reverse transcription was used to analyze the functional characterization of the splice-site mutation in vivo. Evolutionary conservation and molecular modeling analyses were used to predict the impact of missense mutations on secondary protein structure. Immunofluorescence was used to analyze the protein levels of WEE2 and phosphorylated CDC2.

Result(s)

Biallelic mutations in WEE2 were identified in 5 of 24 (20.8%) Chinese patients with fertilization failure or poor fertilization. Among these individuals we found a novel splice-site mutation, two novel missense mutations, and a previously reported frame-shift mutation. Splicing mutation c.1136-2A>G of WEE2 caused an alteration of the reading frame and introduced a premature stop codon (p.Gly379Glufs*6/p.Asp380Leufs*39). The missense mutations c.585G>C (p.Lys195Asn) and c.1228C>T (p.Arg410Trp) produced obvious changes in secondary protein structures. Immunostaining indicated that mutated WEE2 resulted in the loss of phosphorylated CDC2. The phenotypes of women carrying WEE2 mutations exhibited slight variability, from total fertilization failure to poor fertilization.

Conclusion(s)

Novel mutations in the known causative gene WEE2 were identified in 5 of 24 women with fertilization failure or poor fertilization, indicating a high prevalence of WEE2 mutations in Chinese women experiencing fertilization failure or poor fertilization.



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Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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