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Published on: August 15, 2019
Novel homozygous variants in ASTL and WEE2 responsible for female infertility characterized by abnormal fertilization
Siyuan Xie1, Meiling Zhang2,3, Fengyan Wu4
1Institute of Pediatrics, The Institutes of Biomedical Sciences, Children's Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
Purpose:
To identify the disease-causing gene behind infertile couples with female infertility and abnormal fertilization.
Methods:
Whole-exome sequencing and Sanger sequencing were used to identify variants in disease-causing genes in 119 infertile couples with abnormal fertilization. Molecular modeling and functional analysis were used to evaluate the pathogenic effects of the variants.
Results:
We identified one homozygous ASTL variant and three homozygous WEE2 variants from four affected individuals. Among them, WEE2 variants c.1006-1007insTA (p.His337Tyrfs*24) and c.585G > C (p.Lys195Asn) have been previously reported. Structural modeling indicated that the novel ASTL variant c.643G > A (p.Glu215Lys) disrupted the hydrogen bond with Gly-213, while the novel WEE2 variant c.791C > T (p.Ala264Val) significantly decreased tyrosine 15 phosphorylation on Cdc2 and reduced pronucleus formation rate in vitro. In addition, intracytoplasmic sperm injection with assisted oocyte activation (ICSI-AOA) can prevent polyspermy in oocytes with ASTL c.643G > A (p.Glu215Lys) variant and can assist patients in delivering a girl.
Conclusions:
We identified novel homozygous variants in ASTL and WEE2, and functional analysis confirmed the pathogenicity of these variants. In addition, ICSI-AOA rescued the polyspermy phenotype in patients with ASTL c.643G > A (p.Glu215Lys) variant. Our findings further reveal the important role of ASTL and WEE2 in female reproduction and expand the mutational spectrum of the abnormal fertilization related genes ASTL and WEE2.
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