Alternative titles; symbols
HGNC Approved Gene Symbol: CDC20
Cytogenetic location: 1p34.2 Genomic coordinates (GRCh38) : 1:43,358,981-43,363,203 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.2 | Oocyte/zygote/embryo maturation arrest 14 | 620276 | Autosomal recessive | 3 |
CDC20 is a mitotic activator of the anaphase-promoting complex/cyclosome (APC/C) and acts as a major downstream target for inhibition by the spindle assembly checkpoint (summary by Zhao et al., 2021).
Weinstein et al. (1994) identified a protein, designated p55CDC or CDC20, that is homologous to the S. cerevisiae cell division cycle 20 protein, in cycling mammalian cells. This transcript is detectable in all exponentially growing cell lines but disappears when cells are chemically induced to differentiate. The p55CDC protein is essential for cell division. Immunoprecipitation of p55CDC yielded protein complexes with kinase activity that fluctuated during the cell cycle. Since p55CDC did not have the conserved protein kinase domains, this activity must be due to one or more of the associated proteins in the immune complex. The highest levels of protein kinase activity were seen with alpha-casein and myelin basic protein as substrates and demonstrated a pattern of activity distinct from that described for the known cyclin-dependent cell division kinases. The p55CDC protein was also phosphorylated in dividing cells. The 499-amino acid sequence of p55CDC contains 7 repeats homologous to the beta subunit of G proteins. The highest degree of homology in these repeats was found with the S. cerevisiae Cdc20 and Cdc4 proteins, which have been proposed to be involved in the formation of a functional bipolar mitotic spindle in yeast cells. The G beta repeat has been postulated to mediate protein-protein interactions and, in p55CDC, may modulate its association with a unique cell cycle protein kinase.
By radiation hybrid analysis, Weinstein et al. (1998) mapped the CDC20 gene to 9q13-q21; in an erratum, they reported that the gene on 9q13-q21 is a pseudogene and the correct chromosomal assignment of human CDC20 is 1p34.2-p33.
Cahill et al. (1999) had also localized the CDC20 gene to 9q12-q22.
CDC20 is a component of the mammalian cell cycle mechanism. Activation of the anaphase-promoting complex (APC) is required for anaphase initiation and for exit from mitosis. Fang et al. (1998) showed that APC was activated during mitosis and G1 by 2 regulatory factors, CDC20 and HCDH1 (603619). These proteins directly bind to APC and activate its cyclin ubiquitination activity. CDC20 confers a strict destruction-box (D-box) dependence on APC, while HCDH1 shows a much more relaxed specificity for the D-box. In HeLa cells, the protein levels of CDC20 as well as its binding to APC peak in mitosis and decrease drastically at early G1. Thus, CDC20 is the mitotic activator of APC and directs the degradation of substrates containing the D-box.
By investigating the essential role of CKS1 (116900) in S. cerevisiae, Morris et al. (2003) demonstrated that the protein is primarily involved in promoting mitosis by modulating the transcriptional activation of CDC20. CKS1 is required for both the periodic dissociation of CDC28 kinase from the CDC20 promoter and the periodic association of the proteasome with the promoter. Morris et al. (2003) proposed that the essential role of CKS1 is to recruit the proteasome to, and/or dissociate the CDC28 kinase from, the CDC20 promoter, thus facilitating transcription by remodeling transcriptional complexes or chromatin associated with the CDC20 gene.
Tang et al. (2004) found that HeLa cells depleted of BUB1 (602452) by RNA interference were defective in checkpoint signaling. BUB1 directly phosphorylated CDC20 in vitro and inhibited the ubiquitin ligase activity of the APC. A CDC20 mutant lacking all 6 BUB1 phosphorylation sites was refractory to BUB1 mediated phosphorylation and inhibition in vitro. Upon checkpoint activation, BUB1 itself was hyperphosphorylated, and its kinase activity toward CDC20 was stimulated. Ectopic expression of the nonphosphorylatable CDC20 mutant allowed HeLa cells to escape from mitosis in the presence of spindle damage. Tang et al. (2004) concluded that BUB1-mediated phosphorylation of CDC20 is required for proper checkpoint signaling and that inhibition of APC by BUB1 may partly account for the sensitivity of the spindle checkpoint.
Reddy et al. (2007) demonstrated that cell-cycle checkpoint inactivation is an energy-consuming processing involving APC-dependent multiubiquitination. Multiubiquitination by APC leads to the dissociation of Mad2 (601467) and BubR1 (602860) from Cdc20, a process that is reversed by a Cdc20-directed deubiquitinating enzyme. The mutual regulation between checkpoint proteins and APC leaves the cell poised for rapid checkpoint inactivation and ensures that chromosome segregation promptly follows the completion of kinetochore attachment. In addition, Reddy et al. (2007) concluded that their results suggest a mechanistic basis for how cancer cells can have a compromised spindle checkpoint without corresponding mutations in checkpoint genes.
Herzog et al. (2009) used single-particle electron microscopy to obtain 3-dimensional models of human APC/C in various functional states: bound to the mitotic checkpoint complex, to Cdc20, or to neither (apo-APC/C). These experiments revealed that the mitotic checkpoint complex associates with the Cdc20 binding sites on APC, locks the otherwise flexible APC/C in a closed state, and prevents binding and ubiquitylation of a wide range of different APC/C substrates.
Yang et al. (2009) found that the major mitotic E3 ubiquitin ligase Cdc20-APC regulates presynaptic differentiation in primary postmitotic mammalian neurons and in the rat cerebellar cortex. Cdc20-APC triggered the degradation of the transcription factor NeuroD2 (601725) and thereby promoted presynaptic differentiation. The NeuroD2 target gene encoding complexin-2 (CPLX2; 605033), which acts locally at presynaptic sites, mediated the ability of NeuroD2 to suppress presynaptic differentiation. Yang et al. (2009) concluded that their findings defined a Cdc20-APC ubiquitin signaling pathway that governs presynaptic development.
APC/C activation in mitosis requires binding of CDC20, which forms a coreceptor with the APC/C to recognize substrates containing a destruction box (D-box). Sackton et al. (2014) demonstrated that they could synergistically inhibit APC/C-dependent proteolysis and mitotic exit by simultaneously disrupting 2 protein-protein interactions within the APC/C-CDC20-substrate ternary complex. The authors identified a small molecule that they called apcin (APC inhibitor), which binds to CDC20 and competitively inhibits the ubiquitylation of D-box-containing substrates. Analysis of the crystal structure of the apcin-CDC20 complex suggested that apcin occupies the D-box-binding pocket on the side face of the WD40 domain. The ability of apcin to block mitotic exit was synergistically amplified by coaddition of tosyl-L-arginine methyl ester, a small molecule that blocks the APC/C-CDC20 interaction. Sackton et al. (2014) concluded that their work suggested that simultaneous disruption of multiple, weak protein-protein interactions is an effective approach for inactivating a protein machine.
The mitotic checkpoint complex (MCC) is an APC/C inhibitor that incorporates CDC20. Izawa and Pines (2015) showed that the MCC can inhibit a second CDC20 that has already bound and activated the APC/C. The authors showed how the MCC inhibits active APC/C and that this is essential for the spindle assembly checkpoint (SAC). This mechanism can prevent anaphase in the absence of kinetochore signaling. Izawa and Pines (2015) proposed that the diffusible 'wait anaphase' signal could be the MCC itself, and explained how reactivating the SAC can rapidly inhibit active APC/C.
Luo et al. (2002) showed that RNA interference-mediated suppression of MAD1 (602686) function in mammalian cells caused loss of MAD2 (601467) kinetochore localization and impairment of the spindle checkpoint. MAD1 and CDC20 contain MAD2-binding motifs that share a common consensus, and the authors identified a class of MAD2-binding peptides (MBPs) with a similar consensus. Binding of one of these ligands, MBP1, triggered an extensive rearrangement of the tertiary structure of MAD2. MAD2 also underwent a similar striking structural change upon binding to a MAD1 or CDC20 binding motif peptide. These data suggested that, upon checkpoint activation, MAD1 recruits MAD2 to unattached kinetochores and may promote binding of MAD2 to CDC20.
Oocyte/Zygote/Embryo Maturation Arrest 14
In 5 unrelated Chinese women with infertility due to oocyte maturation arrest (OZEMA14; 620276), Zhao et al. (2020) identified homozygosity or compound heterozygosity for mutations in the CDC20 gene (see, e.g., 603618.0002-603618.0006). The mutations segregated with disease in the families for which parental DNA was available, and were either not found or present at low minor allele frequency in public variant databases. In experiments using mouse oocytes with Cdc20 knockdown and an metaphase I (MI) arrest phenotype, the authors demonstrated rescue with wildtype CDC20 cRNA; however, all of the mutations significantly reduced the ability of CDC20 to rescue the phenotype.
In a 27-year-old Chinese woman with infertility due to oocyte maturation abnormalities and early embryonic arrest, Huang et al. (2021) sequenced the CDC20 gene and identified compound heterozygosity for a missense substitution (A211T; 603618.0007) and a nonsense mutation (R262X; 603618.0008). The mutations segregated with disease in the family, and the A211T variant was not found in public variant databases, whereas R262X was listed in dbSNP and was present in the other 2 databases at low minor allele frequency, only in heterozygosity.
In 4 Chinese women from 3 families with infertility due to oocyte maturation arrest, fertilization failure, and early embryonic arrest, Zhao et al. (2021) identified homozygous or compound heterozygous mutations in the CDC20 gene (see, e.g., 603618.0003 and 603618.0009-603618.0011). The mutations segregated with disease in the families for which parental DNA was available, and all were present at very low minor allele frequency in the gnomAD database. Functional analysis in mouse oocytes with knockdown of Cdc20 showed that the homozygous and compound heterozygous mutations significantly reduced the ability of CDC20 to rescue the lack of PB1 extrusion (MI arrest).
In a 33-year-old Chinese woman with infertility due to oocyte maturation arrest at MI and fertilization failure of metaphase II (MII) oocytes, Xu et al. (2021) identified homozygosity for the previously reported Y228C substitution in the CDC20 gene. The proband's mother was heterozygous for the variant; DNA was unavailable from the deceased father. Haplotype analysis suggested that Y228C might be a founder mutation in the Chinese population.
Associations Pending Confirmation
--Mosaic Variegated Aneuploidy Syndrome
For discussion of a possible association between mosaic variegated aneuploidy syndrome (see MVA1, 257300) and variation in the CDC20 gene, see 603618.0001.
--Spermatogenic Failure
In a cohort of 766 Chinese men with azoospermia, Li et al. (2017) sequenced the CDC20 gene and identified 1 man who was heterozygous for a c.1147C-T transition, resulting in an R383C substitution at a highly conserved residue. The mutation, which was confirmed by Sanger sequencing, was not found in 521 fertile Chinese men or in the dbSNP135 or 1000 Genomes Project databases; familial segregation was not reported. Functional analysis in transfected HeLa and HEK293T cells demonstrated an increase in the G2/M cell ratio with the mutant compared to wildtype, suggesting that the R383C mutant could block cells from metaphase to anaphase. Analysis of mRNA expression of 4 regulators in the anaphase-promoting complex (APC; see 608473)/cyclosome-CDC20 pathway showed high expression with the mutant compared to wildtype; similarly elevated expression was observed when the R383C mutant was cotransfected with wildtype CDC20, indicating a dominant-negative effect. The authors suggested that the CDC20 R383C mutant may result in azoospermia.
Jin et al. (2010) generated mutant mouse strains in which the dose of CDC20 was reduced in graded increments. They found that while both mitotic and meiotic divisions of male and female germ cells were characterized by inaccurate chromosome segregation and aneuploidization, only female meiosis I was so severely affected that almost exclusively aneuploid mature eggs were generated. Those eggs fertilized normally, but the resulting zygotes died after the first few embryogenic divisions. In contrast, mutant males appeared to have normal fertility and the fidelity of male meiosis I remained quite high at low Cdc20 levels, with testicular tissue showing normal histology and apoptosis rates.
This variant is classified as a variant of unknown significance because its contribution to mosaic variegated aneuploidy syndrome (see MVA1, 257300) has not been confirmed.
In a 54-year-old 46,XY Japanese woman with instability of chromosome numbers (mosaic variegated aneuploidy syndrome, MVA) and spindle assembly checkpoint failure, who was negative for mutation in known MVA-associated genes, Fujita et al. (2020) performed exome sequencing and identified heterozygosity for a de novo c.856C-A transversion (c.856C-A, NM_001255.3) in the CDC20 gene, resulting in an arg286-to-ser (R286S) substitution at a highly conserved residue within the third WD40 repeat, at the binding site for BUBR1 (BUB1B; 602860). Analysis of patient cells revealed evidence of mosaic variegated aneuploidy syndrome (MVA), with random gain and loss of various chromosomes in 15% of cells, without detectable chromosome breakage. Premature chromatid separation was observed in about 6% of cells, and micronuclei were present in 2.5% of cells, indicating chromosome missegregation. Treatment of patient cells with a microtubule depolymerizing reagent resulted in accumulation of octoploid cells, consistent with aberrant cell cycle exit from metaphase due to spindle assembly checkpoint failure. Mutant CDC20 showed lower binding affinity to BUBR1 during the formation of the mitotic checkpoint complex (MCC), but not during the interaction between MCC and the anaphase-promoting complex (APC; see 608473)/cyclosome-CDC20 complex. The authors noted that whereas heterozygous knockout of CDC20 did not induce spindle assembly checkpoint (SAC) failure, knockin of the mutant CDC20 induced SAC failure and random aneuploidy in cultured cells, indicating that the pathogenicity of the R286S variant likely results from imbalance between the MCC and APC/C-CDC20 complexes. The authors suggested that accelerated chromosome number instability may induce premature aging in humans, possibly associated with early loss of stem cells. The proband exhibited short stature and a progeroid appearance with loss of body and scalp hair, dry atrophic skin with hyper- and hypopigmented macules, and bilateral cataracts, as well as bilateral renal failure, necrosis of the femoral head, bone marrow hypoplasia with severe anemia, and hypothyroidism. She also had streak gonads, low cardiac output, kyphosis, leg-length discrepancy, atrophy of oral mucosa, and nail deformities. Exome sequencing also revealed homozygosity for a splice site mutation in the CENPT gene (611510), predicted to result in an in-frame deletion. Mutant CENPT correctly localized to the kinetochore in patient cells, and further studies involving CENPT were not performed. The authors stated that more patients would be required to determine whether the phenotype was induced by a combination of the CDC20 and CENPT mutations, or by the CDC20 mutation alone.
In a 36-year-old Chinese woman (family 1) with infertility due to oocyte maturation arrest at the germinal vesicle or metaphase I (MI) stage (OZEMA14; 620276), Zhao et al. (2020) identified homozygosity for a c.683A-G transition in exon 5 of the CDC20 gene, resulting in a tyr228-to-cys (Y228C) substitution at a conserved residue. Parental DNA was unavailable for segregation analysis of the variant, which was present in 1 individual in the gnomAD database. Analysis of transfected CHO cells showed a reduction in CDC20 protein level with the Y228C mutant compared to wildtype. During the metaphase to anaphase transition, the anaphase-promoting complex (APC; see 608473)/cyclosome-CDC20 complex is activated through release from CDC20 inhibition, resulting in breakdown of cyclin B1 (CCB1; 123836). As expected, overexpression of wildtype CDC20 in CHO cells significantly decreased cyclin B1 levels, but transfection with the Y228C mutant did not result in increased degradation of cyclin B1. In experiments using mouse oocytes with Cdc20 knockdown and an MI arrest phenotype, the authors demonstrated rescue with wildtype CDC20 cRNA; however, the Y228C mutation significantly reduced the ability of CDC20 to rescue the phenotype.
In a 33-year-old Chinese woman with infertility due to oocyte maturation arrest at MI and fertilization failure of metaphase II (MII) oocytes, Xu et al. (2021) identified homozygosity for the Y228C substitution in the CDC20 gene. The proband's mother was heterozygous for the variant; DNA was unavailable from the deceased father. Haplotype analysis revealed that this patient and patient 1 of Zhao et al. (2020) carried an identical 1.4-Mb haplotype, suggesting that the Y228C variant might be a founder mutation in the Chinese population.
In 3 unrelated Chinese women (probands of families 3, 4, and 5) with infertility due to fertilization failure or early embryonic arrest (OZEMA14; 620276), Zhao et al. (2020) identified compound heterozygosity for a c.965G-A transition in exon 7 of the CDC20 gene, resulting in an arg322-to-gln (R322Q) substitution at a conserved residue, and a truncating mutation in CDC20: in proband 3, the second mutation was a c.544C-T transition (603618.0004) in exon 4, resulting in an arg182-to-ter (R182X) substitution; in proband 4, the second mutation was a 4-bp insertion (c.813_814insAGTG; 603618.0005) in exon 6, causing a frameshift predicted to result in a premature termination codon (Gly272SerfsTer24); and in proband 5, the second mutation was a 4-bp deletion (c.1176_1179delTCTG; 603618.0006) in exon 8, causing a frameshift predicted to result in a premature termination codon (cys392 to ter; C392X). The mutations were confirmed by Sanger sequencing and segregated with disease in each family. The truncating variants were not found in the East Asian populations of the ExAC and gnomAD databases, whereas the R322Q variant was present at low minor allele frequency. Analysis of transfected CHO cells confirmed truncated proteins with the 3 truncating mutations, and although there was no obvious effect on protein level with the R322Q mutation, Western blot analysis of lymphoblastoid cell lines (LCLs) from proband 3 showed a significantly reduced CDC20 protein level. In addition, CDC20 mRNA expression in LCLs from proband 3 and granulosa cells from proband 4 was reduced significantly, and mRNA expression in CHO cells was reduced significantly with the 4-bp deletion in proband 5. During the metaphase to anaphase transition, the anaphase-promoting complex (APC; see 608473)/cyclosome-CDC20 complex is activated through release from CDC20 inhibition, resulting in breakdown of cyclin B1 (CCB1; 123836). As expected, overexpression of wildtype CDC20 in CHO cells significantly decreased cyclin B1 levels, as did overexpression of the R322Q variant, but transfection with the truncating variants did not result in increased degradation of cyclin B1. The truncated proteins also did not show normal kinetochore localization in mouse oocytes, indicating that the truncating variants result in loss of function. In experiments using mouse oocytes with Cdc20 knockdown and an MI arrest phenotype, the authors demonstrated rescue with wildtype CDC20 cRNA; the compound heterozygous mutations in probands 3, 4, and 5 significantly reduced the ability of CDC20 to rescue the phenotype.
In 2 Chinese sisters (family 2) with infertility due to maturation arrest and fertilization failure, Zhao et al. (2021) screened the CDC20 gene and identified compound heterozygosity for the c.965G-A transition (c.965G-A, NM_001255.3) resulting in the R322Q substitution, and a c.964C-T transition, resulting in an arg322-to-ter (R322X; 603618.0009) substitution at the same residue. Their parents were each heterozygous for 1 of the mutations, which were both found at low minor allele frequency in the gnomAD database.
For discussion of the c.544C-T transition in exon 4 of the CDC20 gene, resulting in an arg182-to-ter (R182X) substitution, that was found in compound heterozygous state in a 35-year-old Chinese woman (proband 3) with infertility due to oocyte maturation arrest and fertilization failure (OZEMA14; 620276) by Zhao et al. (2020), see 603618.0003.
For discussion of the 4-bp insertion (c.813_814insAGTG) in exon 6 of the CDC20 gene, causing a frameshift predicted to result in a premature termination codon (Gly272SerfsTer24), that was found in compound heterozygous state in a 34-year-old Chinese woman (proband 4) with infertility due to oocyte maturation arrest and fertilization failure (OZEMA14; 620276) by Zhao et al. (2020), see 603618.0003.
For discussion of the 4-bp deletion (c.1176_1179delTCTG) in exon 8 of the CDC20 gene, causing a frameshift predicted to result in a premature termination codon (cys392-to-ter; C392X), that was found in compound heterozygous state in a 35-year-old Chinese woman (proband 5) with infertility due to early embryonic arrest (OZEMA14; 620276) by Zhao et al. (2020), see 603618.0003.
In a 27-year-old Chinese woman with infertility due to oocyte maturation abnormalities and early embryonic arrest (OZEMA14; 620276), Huang et al. (2021) identified compound heterozygosity for a c.631G-A transition (c.631G-A, NM_001255.3) in exon 6 of the CDC20 gene, resulting in an ala211-to-thr (A211T) substitution at a highly conserved residue, and a c.784C-T transition in exon 7, resulting in an arg262-to-ter (R262X; 603618.0008) substitution. The proband's mother, father, and fertile sister were each heterozygous for 1 of the mutations. The A211T variant was not found in the dbSNP, ExAC, or gnomAD databases, whereas the R262X mutation was listed in dbSNP (rs754957702) and was present in the other 2 databases at low minor allele frequency, only in heterozygosity. In addition to oocyte maturation defects, this patient also had a reduced number of antral follicles as well as complete occlusion of the right fallopian tube and incomplete patency of the left tube.
For discussion of the c.784C-T transition (c.784C-T, NM_001255.3) in exon 7 of the CDC20 gene, resulting in an arg262-to-ter (R262X) substitution, that was found in compound heterozygous state in a 27-year-old Chinese woman with infertility due to oocyte maturation abnormalities and early embryonic arrest (OZEMA14; 620276) by Huang et al. (2021), see 603618.0007.
For discussion of the c.964C-T transition (c.964C-T, NM_001255.3) in exon 7 of the CDC20 gene, resulting in an arg322-to-ter (R322X) substitution, that was found in compound heterozygous state in 2 Chinese sisters (family 2) with infertility due to oocyte maturation arrest and fertilization failure (OZEMA14; 620276) by Zhao et al. (2021), see 603618.0003.
In a 32-year-old Chinese woman (family 3) with infertility due to oocyte maturation arrest and fertilization failure (OZEMA14; 620276), Zhao et al. (2021) identified compound heterozygosity for mutations in the CDC20 gene: a splice site mutation (c.330+1G-A, NM_001255.3) in intron 2, causing retention of intron 2 and resulting in a premature termination codon (Glu111IlefsTer36), and a c.1155G-C transversion in exon 9, resulting in a trp385-to-cys (W385C; 603618.0011) substitution. DNA was not available from her parents for segregation analysis. Both variants were present at very low minor allele frequency in the gnomAD database. Analysis of transfected CHO cells showed reduced CDC20 protein levels with the W385C mutant. Functional analysis in mouse oocytes with knockdown of Cdc20 showed that each mutation significantly reduced the ability of CDC20 to rescue the lack of PB1 extrusion (MI arrest) compared to wildtype.
For discussion of the c.1155G-C transversion (c.1155G-C, NM_001255.3) in exon 8 of the CDC20 gene, resulting in a trp385-to-cys (W385C) substitution, that was found in compound heterozygous state in a 32-year-old Chinese woman (family 3) with infertility due to oocyte maturation arrest and fertilization failure (OZEMA14; 620276) by Zhao et al. (2021), see 603618.0010.
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