Alternative titles; symbols
HGNC Approved Gene Symbol: UBE2T
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:202,331,657-202,341,936 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | Fanconi anemia, complementation group T | 616435 | Autosomal recessive | 3 |
The covalent conjugation of ubiquitin to proteins regulates diverse cellular pathways and proteins. Ubiquitin is transferred to a target protein through a concerted action of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), such as UBE2T, and a ubiquitin ligase (E3) (Machida et al., 2006).
Zhang et al. (2000) cloned UBE2T, which they designated HSPC150, from CD34 (142230)-positive hematopoietic stem/progenitor cells. The deduced 197-amino acid protein contains a ubiquitin-conjugating enzyme active site. EST database analysis indicated widespread UBE2T expression.
Machida et al. (2006) found homologs of UBE2T in only vertebrate databases.
Machida et al. (2006) found that UBE2T is essential for the Fanconi anemia pathway for the efficient repair of damaged DNA. UBE2T bound to the C-terminal PH domain of FANCL (PHF9; 608111), the ubiquitin ligase subunit of the Fanconi anemia core complex, leading to the monoubiquitination of FANCD2 (227646). DNA damage in UBE2T-depleted human osteosarcoma cells led to the formation of abnormal chromosomes that are a hallmark of Fanconi anemia. Machida et al. (2006) also found that UBE2T undergoes automonoubiquitination in vivo. This monoubiquitination was stimulated by the presence of FANCL and inactivated UBE2T. UBE2T activity was dependent on the conserved cys86, where a ubiquitin molecule is transferred from E1, and UBE2T underwent automonoubiquitination at lys91 in vivo. The monoubiquitination of UBE2T occurred even in the absence of an E3 in vitro. Machida et al. (2006) concluded that UBE2T is the E2 in the Fanconi anemia pathway and has a self-inactivation mechanism that could be important for negative regulation of the pathway.
Zhang et al. (2000) determined that the UBE2T gene contains 7 exons.
By radiation hybrid and genomic sequence analyses, Zhang et al. (2000) mapped the UBE2T gene to chromosome 1q31.
In 2 unrelated Japanese patients with Fanconi anemia of complementation group T (FANCT; 616435), Hira et al. (2015) identified mutations in the UBE2T gene. Both patients carried a missense mutation (Q2E; 610538.0001 on 1 allele; 1 patient (PNGS-255) carried a splice site mutation 610538.0002) on the other allele, and the other patient (PNGS-252) carried a 23-kb deletion encompassing almost the entire UBE2T gene and part of the LGR6 gene (606653) on the other allele. The exact breakpoints of the deletion could not be determined.
In 2 unrelated Japanese patients (PNGS-252 and PNGS-255) with Fanconi anemia of complementation group T (FANCT; 616435), Hira et al. (2015) identified a heterozygous c.4C-G transversion (c.4C-G, NM_014176.3) in the UBE2T gene, resulting in a gln2-to-glu (Q2E) substitution at a highly conserved residue in the N-terminal helix, which constitutes part of the hydrophobic E3-E2 interaction surface. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP or Exome Sequencing Project databases. In patient PNGS-252, array CGH identified a 23-kb deletion encompassing almost the entire UBE2T gene on the other allele; the exact breakpoints could not be determined, but the deletion extended to part of the neighboring LGR6 gene (606653). The Q2E mutation was inherited from the unaffected mother, and the deletion was inherited from the unaffected father, confirming familial segregation and indicating autosomal recessive inheritance. Patient PNGS-255 carried a G-to-A transition in intron 2 (c.180+5G-A; 610538.0002) on the other allele. The splice site mutation was demonstrated to result in the skipping of exon 2, causing a frameshift and premature termination (Gln37ArgfsTer47). Cells derived from patient PNGS-252 showed increased levels of mitomycin C-induced chromosome breakage, which was rescued by expression of wildtype UBE2T. In vitro functional expression assays and studies on cells derived from patient PNGS-252 showed that the Q2E mutation abolished FANCD2 (613984) monoubiquitination and interaction with FANCL (608111).
For discussion of the splice site mutation (c.180+5G-A, NM_014176.3) in intron 2 of the UBE2T gene that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group T (FANCT; 616435) by Hira et al. (2015), see 610538.0001.
Hira, A., Yoshida, K., Sato, K., Okuno, Y., Shiraishi, Y., Chiba, K., Tanaka, H., Miyano, S., Shimamoto, A., Tahara, H., Ito, E., Kojima, S., Kurumizaka, H., Ogawa, S., Takata, M., Yabe, H., Yabe, M. Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. Am. J. Hum. Genet. 96: 1001-1007, 2015. [PubMed: 26046368] [Full Text: https://doi.org/10.1016/j.ajhg.2015.04.022]
Machida, Y. J., Machida, Y., Chen, Y., Gurtan, A. M., Kupfer, G. M., D'Andrea, A. D., Dutta, A. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Molec. Cell 23: 589-596, 2006. [PubMed: 16916645] [Full Text: https://doi.org/10.1016/j.molcel.2006.06.024]
Zhang, Q.-H., Ye, M., Wu, X.-Y., Ren, S.-X., Zhao, M., Zhao, C.-J., Fu, G., Shen, Y., Fan, H.-Y., Lu, G., Zhong, M., Xu, X.-R., and 9 others. Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. Genome Res. 10: 1546-1560, 2000. [PubMed: 11042152] [Full Text: https://doi.org/10.1101/gr.140200]