Novel WEE2 gene variants identified in patients with fertilization failure and female infertility

Abstract

Objective: To determine whether variants in the WEE2 (WEE1 homolog 2, also known as WEE1B) gene, which has been known to function in the formation of pronuclei during fertilization, contribute to fertilization failure. Design: Case-control genetic study. Setting: University hospital. Patient(s): Ninety infertile women with repeated cycles of pronucleus formation failure undergoing in vitro fertilization and/or intracytoplasmic sperm injection treatment as well as 200 fertile control women. Intervention(s): Genomic DNA was extracted from the peripheral blood. The whole exons of WEE2 were amplified by means of polymerase chain reaction and then Sanger sequencing was performed. Main Outcome Measure(s): Variants analysis of WEE2 gene. Result(s): We identified five subjects that were subjected to homozygous or compound-heterozygous variants of WEE2: case 1 (from a consanguineous family) with homozygous frameshift variant: c.293_294insCTGAGACACCAGCCCAACC (p.Pro98Pro fsX2); case 2 with homozygous missense variant: c.1576T>G (p.Tyr526Asp); and three cases with compound-heterozygous variants: case 3: c.991C>A (p.His331Asn) and c.1304_1307delCCAA (p.Thr435Met fsX31); case 4: c.341_342 del AA (p.Lys114Asn fsX20) and c.864G>C (p.Gln288His); and case 5: c.1A>G (p.0?) and c.1261G>A (p.Gly421Arg). Besides c.1576T>G (from case 2) and c.864G>C (from case 4), which have been previously reported as rare single nucleotide polymorphisms (SNPs), the other six variants were novel and predicted by software to be deleterious. The parental genotypes of case 1 and case 2 indicated that the detected homozygous variants were inherited in an autosomal recessive mode. All of the detected variants were absent from the control cohort. Conclusion(s): Novel variants found in WEE2, which is autosomal-recessive inherited, may be related to recurrent pronucleus formation failure and female infertility. (Fertil Steril Ò 2019;111:519-26. Ó2018 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

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

“…Nearly all the patients with WEE2 mutations presented with complete obstacles in PN formation on day 1 (D1) from MII oocytes despite the use of ICSI or the calcium ionophore A23187 for activation. However, cases with mutation c.1228C > T, c.1576T > G and c.293_294ins presented with low fertilization rate and none normal cleavage embryos [ 11 , 12 , 14 ]. In our study, we identified a novel compound heterozygous mutation in WEE2 , expanding the mutation spectrum of this gene in 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.…”

A Novel Homozygous Missense Mutation of WEE2 Causes Female Infertility Characterized by Fertilization Failure

“…Clinically, sperm and oocyte morphology are normal, but fertilization always fails, even when oocytes are remedied by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) [3]. Several homozygous and biallelic mutations in WEE2(WEE1 homolog 2, also known as WEE1B) have been reported to be associated with fertilization failure [4][5][6][7][8][9][10][11]. WEE2 (MIM: 614084) gene encoding Wee2 protein belongs to the Wee kinase protein family [12], which is specifically expressed in oocytes and highly conserved in various species.…”