Alternative titles; symbols
HGNC Approved Gene Symbol: TRIP13
Cytogenetic location: 5p15.33 Genomic coordinates (GRCh38): 5:892,884-919,348 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p15.33 | Mosaic variegated aneuploidy syndrome 3 | 617598 | Autosomal recessive | 3 |
| Oocyte/zygote/embryo maturation arrest 9 | 619011 | Autosomal recessive | 3 |
The TRIP13 gene encodes a highly conserved AAA+ATPase that contributes to homolog pairing, synapsis, and recombination during meiosis, and inactivates the spindle assembly checkpoint (SAC) effector MAD2 (see 601467) during mitosis (summary by Yost et al., 2017).
Thyroid hormone receptors (TRs) are hormone-dependent transcription factors that regulate expression of a variety of specific target genes. They must specifically interact with a number of proteins as they progress from their initial translation and nuclear translocation to heterodimerization with retinoid X receptors (RXRs), functional interactions with other transcription factors and the basic transcriptional apparatus, and eventually, degradation. To help elucidate the mechanisms that underlie the transcriptional effects and other potential functions of TRs, Lee et al. (1995) used the yeast interaction trap, a version of the yeast 2-hybrid system, to identify proteins that specifically interact with the ligand-binding domain of rat TR-beta (THRB; 190160). They isolated HeLa cell cDNAs encoding several different TR-interacting proteins (TRIPs), including TRIP13.
Yasugi et al. (1997) identified 16E1BP by its ability to interact with the human papillomavirus type 16 (HPV16) E1 protein in a yeast 2-hybrid assay. The predicted 432-amino acid 16E1BP protein contains a consensus ATP-binding motif. A large region of 16E1BP, which encompasses the putative ATP-binding motif, shares sequence similarity with a YTA-like yeast protein. Yasugi et al. (1997) noted that 16E1BP appears to be a form of TRIP13 (Lee et al., 1995). They discussed the sequence differences between these proteins; notably, a significant portion of 16E1BP, including the ATP-binding motif, is not represented in TRIP13.
Lee et al. (1995) found that TRIP13 interacted with rat Thrb only in the absence of thyroid hormone. It did not interact with RXR-alpha (RXRA; 180245) or the glucocorticoid receptor (NR3C1; 138040) under any condition.
Eytan et al. (2014) identified the AAA-ATPase TRIP13 as a factor that promoted ATP- and p31(COMET) (MAD2L1BP; 618136)-dependent disassembly of the p55CDC (CDC20; 603618)-MAD2 (MAD2L1; 601467) subcomplex of the mitotic checkpoint complex (MCC) in HeLa cell extracts. Using recombinant proteins, they demonstrated that p31(COMET) and TRIP13 acted together to dissociate the p55CDC-MAD2 subcomplex, disassemble the MCC, release the anaphase-promoting complex/cyclosome (APC/C) from checkpoint inhibition, and inactivate the mitotic checkpoint.
Cryoelectron Microscopy
In combination with p31(comet) (MAD2L1BP), a spindle assembly checkpoint (SAC) antagonist, TRIP13 remodels active closed MAD2 (C-MAD2) into inactive open MAD2 (O-MAD2). Alfieri et al. (2018) determined cryoelectron microscopy structures of the TRIP13-p31(comet)-C-MAD2-CDC20 complex, which revealed that p31(comet) recruits C-MAD2 to a defined site on the TRIP13 hexameric ring, positioning the N terminus of C-MAD2 to insert into the axial pore of TRIP13 and distorting the TRIP13 ring to initiate remodeling. Molecular modeling suggested that by gripping C-MAD2 within its axial pore, TRIP13 couples sequential ATP-driven translocation of its hexameric ring along MAD2 to push upwards on, and simultaneously rotate, the globular domains of the p31(comet)-C-MAD2 complex. This unwinds a region of the alpha-A helix of C-MAD2 that is required to stabilize the C-MAD2 beta-sheet, thus destabilizing C-MAD2 in favor of O-MAD2 and dissociating MAD2 from p31(comet). Alfieri et al. (2018) concluded that their study provided insights into how specific substrates are recruited to AAA+ ATPases through adaptor proteins and suggested a model of how translocation through the axial pore of AAA+ ATPases is coupled to protein remodeling.
Gross (2014) mapped the TRIP13 gene to chromosome 5p15.33 based on an alignment of the TRIP13 sequence (GenBank BC000404) with the genomic sequence (GRCh37).
Mosaic Variegated Aneuploidy Syndrome 3
In 6 unrelated patients with mosaic variegated aneuploidy syndrome-3 (MVA3; 617598) manifest as early-onset Wilms tumor, Yost et al. (2017) identified homozygous truncating mutations in the TRIP13 gene (604507.0001-604507.0002). Mutations in the first 3 patients were found by exome sequencing of 43 individuals from 20 families, including 21 probands with MVA. All 3 patients had Wilms tumor. Subsequent exome sequencing of 11 patients of Asian descent with Wilms tumor identified 2 additional patients with the same mutation (R354X; 604507.0001). All 5 patients were of Asian or Pakistani descent, and the mutation segregated in all families from which parental DNA was available. The second mutation (604507.0002) was found in a 2.5-year-old girl of Norwegian descent with Wilms tumor; however, mosaic aneuploidy was not observed in her lymphocytes. Cells derived from patients with the R354X mutation showed chromosomal instability, including aneuploidy, premature chromatid separation, lagging chromosomes, and chromosome bridges. Mutant cells showed increased mitotic exit and impaired recruitment of MAD2 to unattached kinetochores, indicating severe disruption of the spindle assembly checkpoint. These defects could be restored with wildtype TRIP13. The mutant protein was unable to rescue spindle assembly checkpoint defects in a cell line with CRISPR-Cas9-mediated knockdown of TRIP13, consistent with a loss of function.
Oocyte/Zygote/Embryo Maturation Arrest 9
In 5 Chinese women from 4 unrelated families who were infertile due to oocyte maturation arrest at metaphase I (OZEMA9; 619011), Zhang et al. (2020) identified homozygosity or compound heterozygosity for missense mutations in the TRIP13 gene (604507.0003-604507.0007) that segregated with disease. In vitro and in vivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream target HORMAD2 (618842) to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. Injection of patient oocytes with TRIP13 cRNA allowed progression to metaphase II and fertilization by intracytoplasmic sperm injection, with development to the blastocyst stage at 6 days of observation; the authors designated this as 'phenotypic rescue,' with implications for future treatment.
In 5 unrelated patients of Pakistani or Asian origin with mosaic variegated aneuploidy syndrome-3 (MVA3; 617598) manifest as early-onset Wilms tumor, Yost et al. (2017) identified a homozygous c.1060C-T transition (c.1060C-T, NM_004237) in the TRIP13 gene, resulting in an arg354-to-ter (R354X) substitution. The mutation, which was found by exome sequencing in the first 3 individuals, segregated with the disorder in the families from which parental DNA was available. It was not found in the ExAC database or in 11,677 in-house control exomes. The mutation resulted in nonsense-mediated mRNA decay and absence of detectable TRIP13 protein in patient cells, consistent with a loss of function. The mutant protein was unable to rescue spindle assembly checkpoint defects in a cell line with CRISPR-Cas9-mediated knockdown of TRIP13.
In a 2.5-year-old Norwegian girl with mosaic variegated aneuploidy syndrome-3 (MVA3; 617598), Yost et al. (2017) identified a homozygous G-to-C transversion in intron 7 (c.673-1G-C, NM_004237) of the TRIP13 gene, predicted to result in a frameshift and premature termination.
In 3 Chinese women (families 1 and 2) with infertility due to oocyte maturation arrest (OZEMA9; 619011), Zhang et al. (2020) identified homozygosity for a c.77A-G transition (c.77A-G, NM_004237.4) in exon 1 of the TRIP13 gene, resulting in a his26-to-arg (H26R) substitution at a conserved residue. The unaffected parents in both families were heterozygous for the mutation, which was found in the East Asian population of the ExAC database at an allele frequency of 0.0002 and in the gnomAD database at an allele frequency of 9.2 x 10(-6). The parents in family 1 were consanguineous. Immunoblot analysis of transfected HeLa cells showed significantly reduced TRIP13 levels with the H26R mutant compared to wildtype. Similarly, TRIP13 abundance in patient-derived lymphoblastoid cell lines (LCLs) was dramatically reduced compared to control LCLs. In HeLa cells, wildtype TRIP13 had an inhibitory effect on HORMAD2 (618842) levels, but that effect was significantly reduced with the H26R mutant, and HORMAD2 accumulated significantly more at both the mRNA and protein level in patient-derived LCLs compared to control LCLs. Zhang et al. (2020) injected 13 metaphase-I (MI) oocytes from the proband in family 1 with TRIP13 cRNA. All 13 extruded the first polar body, and 11 of the injected oocytes were successfully fertilized; 7 of those developed into blastocysts by day 6 of observation. In contrast, 9 noninjected oocytes remained in the MI stage even after long-term culture.
In a 27-year-old infertile Chinese woman (family 3) with oocyte/zygote/embryo maturation arrest-9 (OZEMA9; 619011), Zhang et al. (2020) identified compound heterozygosity for a c.518G-A transition (c.518G-A, NM_004237.4) in exon 5 of the TRIP13 gene, resulting in an arg173-to-gln (R173Q) substitution, and a c.907G-A transition in exon 10 of the TRIP13 gene, resulting in a glu303-to-lys (E303K; 604507.0005) substitution. Both substitutions involved highly conserved residues. The proband's unaffected mother was heterozygous for the E303K mutation; DNA was unavailable from the father. Neither variant was found in the East Asian population of the ExAC database, but both were present at low allele frequencies in the gnomAD database: 8.0 x 10(-6) for R173Q, and 1.8 x 10(-5) for E303K. Immunoblot analysis of transfected HeLa cells showed significantly reduced TRIP13 levels with the E303K mutant compared to wildtype. In addition, wildtype TRIP13 had an inhibitory effect on HORMAD2 (618842) levels, but that effect was significantly reduced with the E303K mutant.
For discussion of the c.907G-A transition (c.907G-A, NM_004237.4) in exon 10 of the TRIP13 gene, resulting in a glu303-to-lys (E303K) substitution, that was found in compound heterozygous state in a 27-year-old infertile Chinese woman (family 3) with oocyte/zygote/embryo maturation arrest-9 (OZEMA9; 619011) by Zhang et al. (2020), see 604507.0004.
In a 29-year-old infertile Chinese woman (family 4) with oocyte/zygote/embryo maturation arrest-9 (OZEMA9; 619011), Zhang et al. (2020) identified compound heterozygosity for a c.592A-G transition (c.592A-G, NM_004237.4) in exon 6 of the TRIP13 gene, resulting in an ile198-to-val (I198V) substitution, and a c.739G-A transition in exon 8 of the TRIP13 gene, resulting in a val247-to-met (V247M; 604507.0007) substitution. Both substitutions involved highly conserved residues. Her unaffected parents were each heterozygous for 1 of the mutations. Immunoblot analysis of transfected HeLa cells showed significantly reduced TRIP13 levels with the V247M mutant compared to wildtype. In addition, wildtype TRIP13 had an inhibitory effect on HORMAD2 (618842) levels, but that effect was significantly reduced with the V247M mutant. The V247M mutant also showed a significant decrease in ATPase activity compared to wildtype TRIP13.
For discussion of the c.739G-A transition (c.739G-A, NM_004237.4) in exon 8 of the TRIP13 gene, resulting in a val247-to-met (V247M) substitution, that was found in compound heterozygous state in a 29-year-old infertile Chinese woman (family 4) with oocyte/zygote/embryo maturation arrest-9 (OZEMA9; 619011) by Zhang et al. (2020), see 604507.0006.
Alfieri, C., Chang, L., Barford, D. Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13. Nature 559: 274-278, 2018. [PubMed: 29973720] [Full Text: https://doi.org/10.1038/s41586-018-0281-1]
Eytan, E., Wang, K., Miniowitz-Shemtov, S., Sitry-Shevah, D., Kaisari, S., Yen, T. J., Liu, S.-T., Hershko, A. Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p13(comet). Proc. Nat. Acad. Sci. 111: 12019-12024, 2014. [PubMed: 25092294] [Full Text: https://doi.org/10.1073/pnas.1412901111]
Gross, M. B. Personal Communication. Baltimore, Md. 6/25/2014.
Lee, J. W., Choi, H.-S., Gyuris, J., Brent, R., Moore, D. D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Molec. Endocr. 9: 243-254, 1995. [PubMed: 7776974] [Full Text: https://doi.org/10.1210/mend.9.2.7776974]
Yasugi, T., Vidal, M., Sakai, H., Howley, P. M., Benson, J. D. Two classes of human papillomavirus type 16 E1 mutants suggest pleiotropic conformational constraints affecting E1 multimerization, E2 interaction, and interaction with cellular proteins. J. Virol. 71: 5942-5951, 1997. [PubMed: 9223484] [Full Text: https://doi.org/10.1128/JVI.71.8.5942-5951.1997]
Yost, S., de Wolf, B., Hanks, S., Zachariou, A., Marcozzi, C., Clarke, M., de Voer, R. M., Etemad, B., Uijttewaal, E., Ramsay, E., Wylie, H., Elliott, A., and 9 others. Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation. Nature Genet. 49: 1148-1151, 2017. [PubMed: 28553959] [Full Text: https://doi.org/10.1038/ng.3883]
Zhang, Z., Li, B., Fu, J., Li, R., Diao, F., Li, C., Chen, B., Du, J., Zhou, Z., Mu, J., Yan, Z., Wu, L., and 10 others. Bi-allelic missense pathogenic variants in TRIP13 cause female infertility characterized by oocyte maturation arrest. Am. J. Hum. Genet. 107: 15-23, 2020. [PubMed: 32473092] [Full Text: https://doi.org/10.1016/j.ajhg.2020.05.001]