Alternative titles; symbols
HGNC Approved Gene Symbol: WEE2
Cytogenetic location: 7q34 Genomic coordinates (GRCh38): 7:141,708,353-141,731,271 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q34 | Oocyte/zygote/embryo maturation arrest 5 | 617996 | Autosomal recessive | 3 |
WEE2 is a protein tyrosine kinase (EC 2.7.1.112) involved in controlling cell cycle progression (Nakanishi et al., 2000).
By searching an EST database for sequences similar to WEE1 (193525), followed by 5-prime and 3-prime RACE and RT-PCR of HeLa cell RNA, Nakanishi et al. (2000) cloned WEE2, which they called WEE1B. The deduced 561-amino acid protein has a calculated molecular mass of 62.4 kD and shares 49% identity with WEE1. WEE2 contains a putative N-terminal nuclear localization signal followed by a kinase domain. Northern blot analysis detected high expression of a 3.4-kb WEE2 transcript in testis, with little to no expression in other tissues examined. RT-PCR analysis detected mouse Wee2 in mature oocytes, but not in mouse embryos at embryonic days 2.5 or 3.5, suggesting maternal expression. Fluorescence-tagged WEE2 was expressed predominantly in nuclei of transfected HeLa cells.
Hartz (2011) mapped the WEE2 gene to chromosome 7q34 based on an alignment of the WEE2 sequence (GenBank AK131218) with the genomic sequence (GRCh37).
Initiation of mitosis is triggered by CDK1 (116940), which is activated by phosphorylation on thr161 by CDK7 (601955) and cyclin H (601953). Nakanishi et al. (2000) found that WEE2 phosphorylated CDK1 on tyr15 when CDK1 was associated with cyclin B1 (CCNB1; 123836), causing CDK1 inactivation. To a lesser extent, WEE2 phosphorylated CDK2 (116953) associated with cyclin A1 (CCNA1; 604036) or cyclin E1 (CCNE1; 123837), but it had no effect on CDK4 (123829) associated with cyclin D1 (CCND1; 168461). Mutation of lys223 to met within the putative WEE2 kinase domain abrogated its kinase activity. Treatment of cyclin B1-CDK1 with wildtype WEE2 reduced the phosphorylation of histone H1 (142709) by CDK1. Catalytically active WEE2, but not a kinase-dead mutant, complemented a Wee1 mutation in fission yeast. Overexpression of WEE2 in yeast led to cell cycle arrest. Nakanishi et al. (2000) concluded that WEE2 controls the cell cycle by inhibiting CDK1 activation.
Cdc2 (116940) inactivation by Wee1b-mediated phosphorylation is necessary for arrest of the oocyte at G2-prophase. Oh et al. (2011) showed that reactivation of a Wee1B pathway triggers the decrease in Cdc2 activity during egg activation. When Wee1B is downregulated, oocytes fail to form a pronucleus in response to calcium signals. Calcium-calmodulin-dependent kinase II (CaMKII; see 114078) activates Wee1B, and CaMKII-driven exit from metaphase II is inhibited by Wee1B downregulation, demonstrating that exit from metaphase requires not only a proteolytic degradation of cyclin B but also the inhibitory phosphorylation of Cdc2 by Wee1B.
In 4 unrelated infertile Chinese women with an oocyte maturation defect (OZEMA5; 617996), Sang et al. (2018) identified homozygosity for mutations in the WEE2 gene (e.g., 614084.0001-614084.0003).
By targeted sequencing of the WEE2 gene in women with recurrent fertilization failure, Zhang et al. (2019) identified 6 patients with homozygous or compound heterozygous mutations. Two of the 6 patients were from consanguineous families and had missense mutations. The other 4 patients had compound heterozygous mutations, including 3 frameshift, 2 missense, 1 nonsense, 1 splicing, and one 3-bp deletion. Two of the mutations had previously been described, including a 4-bp deletion (614084.0003), which was seen in compound heterozygous state in 2 patients (families 3 and 5). Most of the residues affected by the missense mutations were conserved among different species. In 1 patient with a homozygous missense mutation (R410W; 614084.0004), a few oocytes (3/41) could be fertilized, but none of them developed into normal cleavage embryos, suggesting that WEE2 function might be less severely impaired than in families with complete loss of function due to frameshift and nonsense mutations, in which none of the retrieved oocytes could be fertilized. The authors noted that in this study and their previous study (Sang et al., 2018), they identified a total of 10 patients with WEE2 mutations among 25 patients with typical fertilization failure, suggesting that WEE2 mutations are responsible for approximately 40% of patients with fertilization failure.
In a 37-year-old Chinese woman (family 1) with infertility due to an oocyte maturation defect (OZEMA5; 617996), Sang et al. (2018) identified homozygosity for a c.700G-C transversion (c.700G-C, NM_001105558.1) in exon 4 of the WEE2 gene, resulting in an asp234-to-his (D234H) substitution at a highly conserved residue within the P-kinase domain. Her unaffected mother was heterozygous for the mutation, which was not found in the East Asian population of the 1000 Genomes Project database or in the ExAC database; DNA was unavailable from her deceased father. Immunofluorescence analysis of transfected HeLa cells indicated that nuclear localization of the D234H mutant was not affected, but the protein level was slightly reduced; these results were confirmed in transfected mouse germinal-vesicle oocytes. Western blot analysis of transfected HeLa cells showed that levels of the D234H mutant were significantly lower than those of wildtype WEE2. Serine phosphorylation of WEE2 was significantly reduced with the mutant compared to wildtype, and phosphorylation of CDC2 (CDK1; 116940), required for pronuclei formation, was also reduced. Injection of the D234H mutant into mouse oocytes in metaphase II significantly reduced the rate of pronuclei formation.
In a 34-year-old Chinese woman (family 2) with infertility due to an oocyte maturation defect (OZEMA5; 617996), Sang et al. (2018) identified homozygosity for a 1-bp duplication (c.1473dupA, NM_001105558.1) in exon 10 of the WEE2 gene, causing a frameshift predicted to result in a premature termination codon (Thr493AsnfsTer39). Her unaffected parents were both heterozygous for the mutation, which was not found in the East Asian population of the 1000 Genomes Project database or in the ExAC database. Immunofluorescence analysis of transfected HeLa cells indicated that nuclear localization of the Thr493AsnfsTer39 mutant was not affected, but the protein level was slightly reduced; these results were confirmed in transfected mouse germinal-vesicle oocytes. Western blot of transfected HeLa cells showed that levels of the Thr493AsnfsTer39 mutant were significantly lower than those of wildtype WEE2. Serine phosphorylation of WEE2 was significantly increased with the mutant compared to wildtype, but phosphorylation of CDC2 (CDK1; 116940), required for pronuclei formation, was reduced. Injection of the Thr493AsnfsTer39 mutant into mouse oocytes in metaphase II significantly reduced the rate of pronuclei formation.
In a 29-year-old Chinese woman (family 3) with infertility due to an oocyte maturation defect (OZEMA5; 617996), Sang et al. (2018) identified homozygosity for a 4-bp deletion (c.220_223delAAAG, NM_001105558.1) in exon 1 of the WEE2 gene, causing a frameshift predicted to result in a premature termination codon (Glu75ValfsTer6). Her unaffected parents were both heterozygous for the mutation, as was a sister of unknown fertility status. The mutation was not found in the East Asian population of the 1000 Genomes Project database, but was present in the ExAC database at a frequency of 0.00008296 (10/120,538 alleles). Immunofluorescence staining of patient oocytes showed no WEE2 protein, suggesting loss or degradation of the protein, and analysis of transfected HeLa cells indicated significant degradation of the Glu75ValfsTer6 mutant, with only a very faint immunofluorescence signal observed; these results were confirmed in transfected mouse germinal-vesicle oocytes. Western blot of transfected HeLa cells showed nearly undetectable levels of the Glu75ValfsTer6 mutant. Serine phosphorylation of WEE2 was significantly reduced with the mutant compared to wildtype, and phosphorylation of CDC2 (CDK1; 116940), required for pronuclei formation, was also reduced. Injection of the Glu75ValfsTer6 mutant into mouse oocytes in metaphase II significantly reduced the rate of pronuclei formation.
In a 33-year-old woman (family 3) with infertility due to an oocyte maturation defect, Zhang et al. (2019) identified compound heterozygosity for mutations in the WEE2 gene: c.220delAAAG and a splicing mutation at the end of exon 8 (c.1221G-A; 614084.0005), which led to the inclusion of a 575-bp intronic sequence after exon 8 and skipping of exon 9, predicted to result in a truncated protein (Asp408ValfsTer1). The consanguineous parents were each heterozygous for one of the mutations. The patient had undergone 2 failed cycles of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) in which 27 PB1 oocytes were retrieved, but none were able to be fertilized.
In a 42-year-old woman (family 5) with infertility due to an oocyte maturation defect, Zhang et al. (2019) identified compound heterozygosity for mutations in the WEE2 gene: c.220delAAAG and a c.598C-T transition in exon 4, resulting in an arg100-to-ter (R100X; 614084.0006) substitution. Parental samples were not available for study. The patient had undergone 4 IVF/ICSI attempts in which 7 PB1 oocytes had been retrieved, but none were able to be fertilized.
In a 31-year-old woman (family 1) with infertility due to an oocyte maturation defect (OZEMA5; 617996), Zhang et al. (2019) identified homozygosity for a c.1228C-T transition in exon 9 of the WEE2 gene, resulting in an arg410-to-trp (R410W) substitution. The parents were heterozygous for the mutation. The patient had undergone 3 failed attempts using in vitro fertilization/intracytoplasmic sperm injection; out of 41 oocytes retrieved, 3 could be fertilized, suggesting that WEE2 function might be less severely impaired, but none of these developed into normal cleavage embryos.
For discussion of the splicing mutation (c.1221G-A) in intron 8 of the WEE2 gene, which led to the inclusion of a 575-bp intronic sequence after exon 8 and skipping of exon 9, that was found in compound heterozygous state in a patient with an oocyte maturation defect (OZEMA5; 209880) by Zhang et al. (2019), see 614084.0003.
For discussion of the c.598C-T transition in exon 4 of the WEE2 gene, resulting in an arg200-to-ter (R200X) substitution, that was found in compound heterozygous state in a patient with an oocyte maturation defect (OZEMA5; 209880) by Zhang et al. (2019), see 614084.0003.
Hartz, P. A. Personal Communication. Baltimore, Md. 7/11/2011.
Nakanishi, M., Ando, H., Watanabe, N., Kitamura, K., Ito, K., Okayama, H., Miyamoto, T., Agui, T., Sasaki, M. Identification and characterization of human Wee1B, a new member of the Wee1 family of Cdk-inhibitory kinases. Genes Cells 5: 839-847, 2000. [PubMed: 11029659] [Full Text: https://doi.org/10.1046/j.1365-2443.2000.00367.x]
Oh, J. S., Susor, A., Conti, M. Protein tyrosine kinase Wee1B is essential for metaphase II exit in mouse oocytes. Science 332: 462-465, 2011. [PubMed: 21454751] [Full Text: https://doi.org/10.1126/science.1199211]
Sang, Q., Li, B., Kuang, Y., Wang, X., Zhang, Z., Chen, B., Wu, L., Lyu, Q., Fu, Y., Yan, Z., Mao, X., Xu, Y., Mu, J., Li, Q., Jin, L., He, L., Wang, L. Homozygous mutations in WEE2 cause fertilization failure and female infertility. Am. J. Hum. Genet. 102: 649-657, 2018. [PubMed: 29606300] [Full Text: https://doi.org/10.1016/j.ajhg.2018.02.015]
Zhang, Z., Mu, J., Zhao, J., Zhou, Z., Chen, B., Wu, L., Yan, Z., Wang, W., Zhao, L., Dong, J., Sun, X., Kuang, Y., Li, B., Wang, L., Sang, Q. Novel mutations in WEE2: expanding the spectrum of mutations responsible for human fertilization failure. Clin. Genet. 95: 520-524, 2019. [PubMed: 30628060] [Full Text: https://doi.org/10.1111/cge.13505]