Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: UBA1
SNOMEDCT: 719836007;
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38): X:47,190,847-47,215,128 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.3 | Spinal muscular atrophy, X-linked 2, infantile | 301830 | X-linked recessive | 3 |
| VEXAS syndrome, somatic | 301054 | 3 |
The UBE1 (UBA1) gene encodes a ubiquitin activating enzyme (E1) that initiates the activation and conjugation of ubiquitin (UBB; 191339)-like proteins. Modification of proteins with ubiquitin or ubiquitin-like proteins controls many signaling networks and requires a ubiquitin activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a ubiquitin protein ligase (E3) (Jin et al., 2007).
Zacksenhaus and Sheinin (1989) cloned the human A1S9 cDNA following DNA-mediated gene transfer.
Zacksenhaus and Sheinin (1990) isolated a human A1S9 cDNA from a cDNA library. The predicted 803-amino acid protein was found to be conserved in vertebrates and contains 2 potential nuclear localization signals and no DNA binding domains. Northern blot analysis demonstrated lower expression in quiescent cells but higher and constant expression throughout the cell cycle.
Handley et al. (1991) described the cloning and sequencing of the cDNA for human E1, their term for the ubiquitin-activating enzyme catalyzing the first step in ubiquitin conjugation. The cDNA recognized a single 3.5-kb E1 message that was ubiquitous among tissues and cell lines studied. In vitro translation of the mRNA yielded a major product of approximately 118 kD, which was immunoprecipitated by the antihuman E1 antibody used to identify the clone.
Jin et al. (2007) stated that the 1,058-amino acid UBE1 protein contains an N-terminal adenylation domain with 2 ThiF-1 regions, a catalytic cysteine domain, and a C-terminal ubiquitin-fold domain that functions to recruit E2s. Database analysis detected variable UBE1 expression in all human tissues and cell lines examined.
The UBE1 gene contains 27 exons, including an alternative first exon designated 1a (Ramser et al., 2008). Translation begins in exon 2.
Jin et al. (2007) showed that UBE1 was able to transfer ubiquitin to a wide range of E2 substrates.
Ohtsubo and Nishimoto (1988) studied 2 cell lines with a temperature-sensitive (ts) defect in the S-phase of cell cycle. Two lines failed to complement each other and therefore are presumed to have the same defect as demonstrated in 1 of them: a ts defect in the ubiquitin-activating enzyme. X-linkage was shown for one of the cell lines by demonstration of cosegregation with HPRT in interspecies somatic cell hybrids. The complicated nature of the genetic control of cell growth reflected in ts mutants is indicated by the fact that 23 complementation groups have been identified by cell fusion analysis using polyethylene glycol (Nishimoto and Basilico, 1978; Nishimoto et al., 1982).
It turned out that the UBE1 locus is the same as that of the temperature-sensitive gene called A1S9T. Willard et al. (1987) studied the human gene that complements an X-linked mouse temperature-sensitive defect in DNA synthesis; it is apparently different from the X-linked factor represented by entry 313650 inasmuch as it was found to be located on the short arm rather than on the long arm. The mouse mutant tsA1S9 was characterized as a defect in DNA synthesis affecting conversion of low molecular weight, newly synthesized DNA to mature chromosomal DNA. In hybrid cells between normal human cells and mutant mouse cells, it was found that the X chromosome and specifically the short arm of the X chromosome complemented the defect. Brown et al. (1989) and Brown and Willard (1989) found that a somatic hybrid cell containing the region Xp21.1-p11.1 as its only X-chromosomal material was able to survive at the nonpermissive temperature and thus must contain the A1S9T gene. Since they had previously found that this gene can be expressed from an inactive X chromosome (although not from the Y), the new findings indicated that a second region of the human X chromosome, in addition to the distal Xp22.3 location of other genes that escape inactivation (MIC2, STS, XG), is also not subject to X chromosome inactivation.
Zacksenhaus and Sheinin (1988) isolated a human gene complementing the defect in a temperature-sensitive mouse L-cell line called ts A1S9. The defect is in a gene required for nuclear DNA replication early in the S phase of the cell cycle. DNA-mediated gene transfer (DMGT) was used and the highly repetitive Alu family, which is present in at least 1 copy in virtually every human gene, was used as a marker for the presence of the human DNA in transfected mouse cells. Zacksenhaus and Sheinin (1988) stated that this was the first demonstration of transfer of a human S-phase gene. That the gene is X-linked was suggested by the fact that both active and inactive human X chromosomes corrected the defect. The authors quoted observations indicating that the tsA1S9 gene product is not required for polydeoxyribonucleotide chain synthesis per se; thus, the gene does not encode DNA polymerase alpha or DNA ligase. DNA polymerase beta and gamma, as well as poly(ADP-ribose) polymerase, had also been ruled out. Some evidence suggested that the temperature-labile A1S9 protein may participate in DNA topoisomerase-2 activity.
Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich elements in the 3-prime untranslated region. Rapid decay involves AU-rich binding protein AUF1 (601324), which complexes with heat-shock proteins HSC70 (600816) and HSP70 (see 140550), translation initiation factor EIF4G (600495), and poly(A)-binding protein (604679). AU-rich mRNA decay is associated with displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of HSP70 by heat shock, downregulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1, all result in HSP70 sequestration of AUF1 in the perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway (Laroia et al., 1999).
Using Southern blot and in situ hybridization, Zacksenhaus et al. (1989, 1990) mapped the A1S9 gene to Xp11.4-p11.2. On the basis of a study of somatic cell hybrids with various deleted human X chromosomes, Brown and Willard (1990) gave Xp11.3-p11.1 as the location of the A1S9T gene. Combining these data with those of Zacksenhaus et al. (1989, 1990), one might conclude that the location is Xp11.3-p11.2. By high-resolution fluorescence in situ hybridization, Takahashi et al. (1991, 1992) mapped the UBE1 gene to Xp11.3-p11.23.
Mitchell et al. (1991) and Kay et al. (1991) demonstrated homology of a candidate spermatogenesis gene on the mouse Y chromosome to the UBE1 gene on the X chromosome. Mitchell et al. (1991) reported the isolation of a new testis-specific gene, Sby, mapping to the DNA deleted from the Sxr (sex-reversed) region in the mouse. It showed extensive homology to UBE1. Because of its critical role in nuclear DNA replication, together with the testis-specific expression, it was considered a candidate for the spermatogenic gene Spy, which was known to be required for the survival and proliferation of A spermatogonia during spermatogenesis. Kay et al. (1991) isolated part of the mouse A1s9 gene, mapped it to the proximal portion of the X chromosome, and showed that it undergoes normal X-inactivation. They also detected 2 copies of the gene on the short arm of the mouse Y chromosome, A1s9Y1 and A1s9Y2. They found that A1s9Y1 is expressed in testis and is lost in the deletion form of Sxr. A1s9X is similar to the Zfx gene (314980), which undergoes X-inactivation, yet has homologous sequences on the short arm of the Y chromosome that are expressed in the testis. These Y-linked genes may form part of a coregulated group of genes which function during spermatogenesis.
Mammalian sex chromosomes are thought to be descended from a homologous pair of autosomes: a testis-determining allele which defined the Y chromosome arose, recombination between the nascent X and Y chromosomes became restricted, and the Y chromosome gradually lost its nonessential genetic functions. This model was originally inferred from the occurrence of a few Y-linked genetic traits, pairing of the X and Y chromosomes during male meiosis, and the existence of X-Y homologous genes. UBE1 is an X-linked gene with a distinct Y-linked homolog in many eutherian (placental) and metatherian (marsupial) mammals. Nonetheless, no UBE1 homolog is detectable on the human Y chromosome. Mitchell et al. (1998) studied extensively the UBE1 homologs in primates and a prototherian mammal, the platypus. Their findings indicated that UBE1 lies within the X-Y pairing segment of the platypus but is absent from the human Y chromosome, having been lost from the Y chromosome during evolution of the primate lineage.
Spinal Muscular Atrophy 2, X-Linked
Patients with X-linked spinal muscular atrophy-2 (SMAX2; 301830) present with hypotonia, areflexia, and multiple congenital contractures associated with loss of anterior horn cells and infantile death. To identify the disease gene, Ramser et al. (2008) performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132, the critical interval on Xp11.3-q11.1 indicated by linkage studies. This resulted in detection of 3 rare novel variants in exon 15 of UBE1 (UBA1) that segregated with the disease: 2 missense mutations present in each of 1 XLSMA family (314370.0001, 314370.0002), and 1 synonymous C-to-T substitution (314370.0003) identified in another 3 unrelated families. In a sixth family, neither of the 2 missense mutations or the synonymous substitution was identified. Ramser et al. (2008) demonstrated that the synonymous C-to-T substitution leads to significant reduction of UBA1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBA1 expression in humans. Thus, SMAX2 is one of several neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway. The authors concluded that their experience indicated that synonymous C-to-T transitions have the potential to affect gene expression.
VEXAS Syndrome
Using a genotype-driven approach, Beck et al. (2020) identified an adult-onset inflammatory disorder that exclusively affects males and is associated with de novo somatic mutations in the UBA1 gene. The authors reported 25 unrelated men, all above 45 years of age, with UBA1 mutations who were diagnosed with VEXAS syndrome (VEXAS; 301054), an acronym for 'vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic.' The patients were ascertained from several large cohorts of over 2,500 patients with undiagnosed or unclassified inflammatory or systemic disorders who underwent genetic investigation. Each patient had 1 of 3 mutations affecting codon Met41 (M41V, 310370.0004; M41T, 310370.0005; and M41L, 310370.0006), which is the translation initiation site for the cytoplasmic UBA1b isoform. The mutations, which were found by exome or targeted sequencing and confirmed by Sanger sequencing, were absent from public databases, including gnomAD. None of the patients had a family history of a similar disorder. All affected men were somatic mosaic for the UBA1 mutation, which was present in peripheral myeloid cells, granulocytes, and monocytes, but not in fibroblasts or mature lymphoid cells. In contrast, bone marrow examination showed that the UBA1 mutations were present in hematopoietic stem cells and in multipotent early marrow progenitor cells. However, patients also had decreased peripheral lymphocyte counts, suggesting that mutant lymphocytes either did not proliferate or did not survive. UBA1 is normally expressed as 2 isoforms differing at the translation site: nuclear UBA1a (initiation at Met1) and cytoplasmic UBA1b (initiation at Met41). In vitro expression of the Met41 mutations into HEK293T cells resulted in loss of UBA1b and the presence of a shorter abnormal isoform, designated UBA1c, that was initiated from a downstream Met67 codon. UBA1c localized to the cytoplasm, but was catalytically impaired compared to UBA1a and UBA1b. The findings suggested that the mutations identified in patients with VEXAS syndrome favored the production of functionally defective cytoplasmic UBA1 isoform. Mutant monocytes derived from the patients showed loss of ubiquitylation, which caused upregulation of the stress and unfolded protein responses, as well as dysregulation of autophagy. These findings suggested that the inflammation observed was mainly due to mutant myeloid cells, although there was also evidence of disrupted B and T cell and neutrophil activation. Transcriptome analysis of patient peripheral blood cells showed a gene expression pattern consistent with the activation of multiple innate immune pathways, including TNF (191160), IL6 (147620), and IFNG (147570). Beck et al. (2020) noted that many patients had myelodysplasia in addition to systemic inflammation and rheumatologic manifestations; they concluded that subcellular ubiquitin regulation and activation play an important role during hematopoiesis and regulation of the immune response.
Poulter et al. (2021) identified somatic mutations in the UBA1 gene in 10 unrelated men with VEXAS syndrome. The mutations were identified by Sanger sequencing in peripheral blood or bone marrow from the patients. Eight patients had previously reported mutations; 3 had the M41V mutation and 5 had the M41T mutation. One patient had an S56P mutation (314370.0007), which did not affect UBA1 cellular localization or result in isoform expression abnormalities in HEK293 cells transfected with the mutant transcript. Poulter et al. (2021) demonstrated that the S56P mutation resulted in temperature-dependent impairment of UBA1 catalytic activity. Another patient had a splicing mutation (314370.0008), which resulted in multiple incorrectly spliced transcripts and a reduction in the correctly spliced transcript.
In a 68-year-old man with VEXAS syndrome, Lytle and Bagg (2021) reported a somatic mutation at Met41 of the UBA1 gene that was identified by whole-exome sequencing. The patient had a history of macrocytic anemia, myeloma, pancytopenia, and relapsing polychrondritis.
Among a cohort of undiagnosed patients with inborn errors of immunity from academic hospitals in the Netherlands, van der Made et al. (2022) performed systematic reanalysis of exome sequencing data and targeted Sanger sequencing on those without exome data and identified 12 male patients with VEXAS syndrome and somatic mutations at met41 in the UBA1 gene: 7 with M41T, 4 with M41V, and 1 with M41L. The variant allele fraction varied from 17% to 85%. The authors noted that the low level of variant allele fraction (17%) associated with VEXAS syndrome in one of their patients emphasized the importance of specifically evaluating somatic variants during exome analysis to avoid inappropriate elimination of variants if the variant allele fraction is below a certain threshold.
Ferrada et al. (2022) analyzed 83 patients with VEXAS syndrome due to a somatic pathogenic variant at residue Met41 in the UBA1 gene, which is the start codon for the cytoplasmic UBA1b isoform (see M41V, 314370.0004; M41T, 314370.0005; and M41L 314370.0006). All patients were male and Caucasian with a median age at symptom onset of 66 years. Clinical features were characteristic for the disease, but there were some differences associated with the specific variants. Those with M41V were more likely to have an undifferentiated inflammatory syndrome and showed decreased survival compared to those with M41T or M41L. Patients with M41V were less likely to develop ear chondritis, which was associated with overall better survival in the cohort. Patients with M41T had more inflammatory eye disease compared to the others. Decreased survival was also observed in those who were transfusion-dependent. Detailed in vitro studies of the mutations in HEK293 cells and in patient peripheral mononuclear cells demonstrated that all the mutations resulted in decreased levels of UBA1b, with the largest decrease in cells carrying the M41V mutation (about 2-fold lower than M41L or M41T). These findings indicated that M41V supports less translation of UBA1b than the other variants, and showed that VEXAS syndrome severity inversely correlates with residual UBA1b levels. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and affects disease prognosis.
Beck et al. (2020) found that zebrafish with loss of uba1 had growth abnormalities and early death compared to controls. The defects were associated with upregulation of the expression of inflammatory genes.
In a family with infantile X-linked spinal muscular atrophy (SMAX2; 301830), Ramser et al. (2008) detected a G-to-T transversion of nucleotide 1617 in exon 15 of the UBE1 (UBA1) gene that resulted in substitution of ile for met at codon 539 (M539I).
In a family with infantile X-linked spinal muscular atrophy (SMAX2; 301830), Ramser et al. (2008) detected a A-to-G transition of nucleotide 1639 in exon 15 of the UBE1 gene that resulted in substitution of gly for ser at codon 547 (S547G).
In 3 families with infantile X-linked spinal muscular atrophy (SMAX2; 301830), Ramser et al. (2008) detected a novel synonymous C-to-T transition at nucleotide 1731 in exon 15 of the UBE1 gene. This substitution led to significant reduction of UBE1 expression and alteration of the methylation pattern of exon 15.
In 5 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic c.121A-G transition (c.121A-G, NM_003334.3) in the UBA1 gene, resulting in a met41-to-val (M41V) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function.
By Sanger sequencing of the UBA1 gene in 3 unrelated men with VEXAS, Poulter et al. (2021) identified a somatic M41V substitution.
In 4 of 12 patients with VEXAS syndrome, van der Made et al. (2022) identified a somatic M41V mutation in the UBA1 gene.
Variant Function
Through detailed in vitro studies of the M41V mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, Ferrada et al. (2022) demonstrated that it resulted in decreased levels of UBA1b, about 2-fold lower than M41L or M41T. These findings indicated that M41V does not support translation of UBA1b as well as the other variants, and showed that VEXAS syndrome severity inversely correlates with residual UBA1b levels. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and affects disease prognosis.
In 15 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic c.122T-C transition (c.122T-C, NM_003334.3) in the UBA1 gene, resulting in a met41-to-thr (M41T) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function.
By Sanger sequencing of the UBA1 gene in 5 unrelated men with VEXAS, Poulter et al. (2021) identified a somatic M41T substitution.
In 7 of 12 patients with VEXAS syndrome, van der Made et al. (2022) identified a somatic M41T mutation in the UBA1 gene.
Variant Function
Through detailed in vitro studies of the M41T mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, Ferrada et al. (2022) demonstrated that it resulted in decreased levels of UBA1b, indicating impaired translation of the isoform. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and may affect disease prognosis.
In 5 unrelated men with VEXAS syndrome (VEXAS; 301054), Beck et al. (2020) identified a somatic heterozygous c.121A-C transversion (c.121A-C, NM_003334.3) in the UBA1 gene, resulting in a met41-to-leu (M41L) substitution at the translation initiation site for the cytoplasmic UBA1b isoform. The mutation, which was found by exome or targeted sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Expression of the variant into HEK293T cells resulted in loss of UBA1b and the presence of a shortened isoform, designated UBA1c, that was initiated from a Met67 codon. UBA1c localized to the cytoplasm. In vitro functional expression studies showed that the UBA1c isoform was catalytically impaired compared to UBA1a and UBA1b, consistent with a loss of function.
In 1 of 12 patients with VEXAS syndrome, van der Made et al. (2022) identified a somatic M41L mutation in the UBA1 gene.
Variant Function
Through detailed in vitro studies of the M41L mutation in HEK293 cells and in VEXAS patient peripheral mononuclear cells, Ferrada et al. (2022) demonstrated that it resulted in decreased levels of UBA1b, indicating impaired translation of the isoform. The authors concluded that there is a certain minimal threshold of cellular UBA1b levels required to initiate disease progression, and that the major cause of disease is loss of UBA1b or its activity, rather than gain of UBA1c. This regulation of residual UBA1b translation thus appears to be fundamental to the pathogenesis of VEXAS syndrome and may affect disease prognosis.
In a man (patient 9) with VEXAS syndrome (VEXAS; 301054), Poulter et al. (2021) identified a somatic c.167C-T transition (c.167C-T, NM_153280) in the UBA1 gene, resulting in a ser56-to-phe (S56P) substitution. The mutation was identified by Sanger sequencing of the UBA1 gene and was not present in the gnomAD database. Testing in patient blood cells showed that myeloid cells predominantly had the mutant S56P allele, whereas B- and T-cell lineage populations predominantly were wildtype. The mutation did not affect UBA1 cellular localization or result in isoform expression abnormalities in HEK293 cells transfected with the mutant transcript. Poulter et al. (2021) demonstrated that the mutation resulted in temperature-dependent impairment of UBA1 catalytic activity.
In a man (patient 10) with VEXAS syndrome (VEXAS; 301054), Poulter et al. (2021) identified a somatic c.118-1G-C transversion (c.118-1G-C, NM_153280) at the acceptor splice site of exon 3 of the UBA1 gene, predicted to result in a splicing abnormality. The mutation was identified by Sanger sequencing of the UBA1 gene and was not present in the gnomAD database. Analysis of patient RNA demonstrated multiple incorrectly spliced transcripts and a reduction in the correctly spliced transcript.
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