Homozygous missense mutation Arg207Cys in the WEE2 gene causes female infertility and fertilization failure

Abstract

Purpose To investigate a novel mutation in the WEE2 gene in a female patient with primary infertility and fertilization failure. Methods Sanger sequencing was used to detect mutations in WEE2. The pathogenicity of the identified variant and its possible effects on the WEE2 protein were evaluated with in silico tools and molecular modeling. We used the calcium ionophore A23187 as a chemical activator of oocytes after intracytoplasmic sperm injection (ICSI). Results We identified a consanguineous family with a novel homozygous missense mutation in WEE2 (c.619C>T [p.R207C]). Based on preliminary bioinformatics analysis, we speculate that the novel homozygous missense mutation is pathogenic. ICSI combined with assisted oocyte activation (ICSI-AOA) did not overcome fertilization failure in this patient with WEE2 mutation. Conclusions We identified a novel mutation in WEE2 (c.619C>T [p.R207C]) in a female patient with fertilization failure after ICSI, and we provide evidence that this novel homozygous missense mutation can cause fertilization failure.

Origins and mechanisms leading to aneuploidy in human eggs

“…In contrast to association studies, which are generally based on SNP array genotyping at sites of known variation in the human population, the discovery of rare variants that influence aneuploidy risk requires alternative approaches, such as whole genome or targeted sequencing, as well as functional validation in model organisms or human cell lines. For example, targeted sequencing of candidate genes in patients experiencing recurrent IVF failure identified loss‐of‐function variants in a primate‐specific tubulin b class VIII ( TUBB 8), 89–91 PAT1 homolog 2 ( PATL2 ), 92–97 and WEE2 oocyte meiosis inhibiting kinase ( WEE2 ) 98–102 that may predispose women to a higher incidence of oocyte and embryonic aneuploidy at younger‐than‐average ages. The products of these genes are required for essential steps in oocyte development and meiosis.…”

“…7,82,83 Yet depending on their timing of occurrence, even these complex forms of mosaicism may not preclude development, and indeed may be preferentially excluded from the embryo during the process of blastocyst formation. 84,85 While explaining a small fraction (∼1%) of the total variance in aneu- oocyte meiosis inhibiting kinase (WEE2) [98][99][100][101][102] that may predispose women to a higher incidence of oocyte and embryonic aneuploidy at younger-than-average ages. The products of these genes are required for essential steps in oocyte development and meiosis.…”

Novel compound heterozygous mutation in WEE2 is associated with fertilization failure: case report of an infertile woman and literature review

“…As a result, downregulation of Wee2 during egg activation leads to failure of pronucleus formation even after calcium oscillations [ 9 ]. Recently, mutations in WEE2 were found to be associated with human pronucleus formation and repeated fertilization failure [ 6 , 10 – 14 ]. In this study, whole-exome sequencing was performed to clarify the genetic cause of repeated fertilization failure after ICSI-AOA in a non-consanguineous family.…”

Prospects of Germline Nuclear Transfer in Women With Diminished Ovarian Reserve

“…Oocyte factors are attributed to compromised cytoplasmic quality, such as reduced mitochondrial numbers or abnormal proteins involved in fertilization ( 83 , 84 ). Up to now, only mutations in four female genes ( PATL2 , WEE2 , TLE6 and TUBB8 ) have been linked to FF ( 85 ), while AOA was not beneficial for women with WEE2 mutations ( 86 , 87 ). Nevertheless, injection of the WEE2 cRNA led to successful activation of the affected oocytes, allowing the formation of blastocysts ( 85 ), suggesting that cytoplasmic incompetence can be overcome by enriching the oocyte with the normal cRNA.…”