HGNC Approved Gene Symbol:UBA2
Cytogenetic location:19q13.11 Genomic coordinates(GRCh38) :19:34,428,381-34,471,251 (from NCBI)
Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1;601912), or sumoylation, regulates protein structure and intracellular localization. SAE1 (613294) and UBA2 form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins (Okuma et al., 1999).
By sequencing peptide fragments of the purified HeLa cell SUMO1-activating enzyme (SAE), followed by EST database analysis and RT-PCR,Desterro et al. (1999) cloned SAE1 and UBA2, which they called SAE2. The deduced SAE1 and SAE2 proteins contain 347 and 640 amino acids, respectively. SAE1 shares sequence similarity with the N terminus of ubiquitin-activating E1 enzymes (see UBE1;314370), and SAE2 share sequence similarity with the C terminus of E1 enzymes. Both SAE subunits contain a conserved nucleotide-binding motif, and SAE2 contains an E1-like active-site cysteine. SAE2 has a calculated molecular mass of 72 kD. It had an apparent molecular mass of 90 kD by SDS-PAGE.
By searching an EST database for sequences similar to the ATP-binding region of UBE1, followed by RACE of a placenta cDNA library,Gong et al. (1999) cloned UBA2. UBA2 contains 2 ATG translation initiation codons. SDS-PAGE detected UBA2 at apparent molecular masses of 72 and 62 kD, suggesting usage of both ATG codons.
By searching an EST database for sequences similar to yeast Aos1 and Uba2, followed by screening a HeLa cell cDNA library,Okuma et al. (1999) cloned human SUA1 (SAE1) and UBA2, respectively.
Using Northern blot analysis,Azuma et al. (2001) detected both Aos1 and Uba2 in all adult mouse tissues examined, as well as in mouse embryos. Immunofluorescence analysis of HeLa cells showed AOS1 and UBA2 distributed throughout nuclei, but they were excluded from nucleoli. AOS1 and UBA2 copurified through a number of chromatography steps, suggesting they form a tight complex.
By whole-mount in situ hybridization in zebrafish,Schnur et al. (2021) detected uba2 transcript on the dorsoventral axis of 5-somite stage embryos. At later stages, uba2 was expressed in developing brain, eye, craniofacial structures, and fins. At 24 hours postfertilization (hpf), uba2 expression was restricted to the head region, including the eye and nervous system. At 35 hpf, prominent signal was observed in pectoral fins, whereas at later stages uba2 mRNA signal localized to the head region, specifically brain, neural retina, and lens. The authors noted that zebrafish uba2 is expressed in some structures analogous to those affected in humans harboring deleterious UBA2 variants (see MOLECULAR GENETICS).
By genomic sequence analysis,Gong et al. (1999) mapped the UBA2 gene to chromosome 19q12.
Schnur et al. (2021) stated that the UBA2 gene maps to chromosome 19q13.11.
Desterro et al. (1999) showed that purified SAE from HeLa cells bound to immobilized SUMO1 in the presence of ATP. Use of in vitro transcribed and translated SAE1 and SAE2 showed that SUMO1 binding required both SAE subunits and involved a direct thioester linkage between cys173 of SAE2 and SUMO1. Both SAE1 and SAE2 were required to transfer SUMO1 to the SUMO1-conjugating enzyme UBC9 (UBE2I;601661). In the presence of SAE1, SAE2, UBC9, and ATP, SUMO1 was conjugated to recombinant I-kappa-B-alpha (NFKBIA;164008).Desterro et al. (1999) concluded that the SAE1/SAE2 dimer functions in SUMO1 activation in a manner analogous to the single E1 ubiquitin-activating enzymes.
Gong et al. (1999) showed that in vitro-translated human UBA2 could precipitate with epitope-tagged sentrin-1 (SUMO1), ubiquitin (see191339), and NEDD8 (603171) in the presence or absence of ATP. However, conjugation was only detected between UBA2 and sentrin-1, and this occurred only in the presence of AOS1. Sentrin-2 (SUMO2;603042) and sentrin-3 (SUMO3;602231) could also conjugate to UBA2 in the presence of AOS1.
The sumoylated form of RANGAP1 (602362) associates with the nuclear pore complex and is required for import of proteins into the nucleus.Okuma et al. (1999) showed that SUA1, UBA2, and UBC9 catalyzed in vitro sumoylation of RANGAP1. Faint RANGAP1 modification was observed in the absence of UBC9.Okuma et al. (1999) concluded that, in contrast to the 3-step ubiquitination reaction, which requires an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase, sumoylation is a 2-step reaction in which the SUA1/UBA2 dimer functions as an E1 enzyme and UBC9 functions as an E2 enzyme.
By screening for short hairpin RNAs (shRNAs) that altered the fitness of mammary epithelial cells only in the presence of aberrant MYC (190080) signaling,Kessler et al. (2012) identified SAE1 and SAE2 as MYC-synthetic lethal genes. Inactivation of SAE2 led to mitotic catastrophe and cell death upon MYC hyperactivation. SAE2 inhibition switched a MYC transcriptional subprogram from activated to repressed. A subset of sumoylation-dependent MYC switchers (SMS genes), including CASC5 (609173), BARD1 (601593), and CDC20 (603618), was required for mitotic spindle function and to support the MYC oncogenic program. Sae2 was required for growth of Myc-dependent tumors in mice. Transduction of MYC-dependent breast cancer cells with inducible SAE2 shRNA suggested that SAE2 was required for growth and fitness of these cell lines. Gene expression analysis of human breast cancers with hyperactive MYC suggested that low expression of SAE1 and SAE2 resulted in better metastasis-free survival.Kessler et al. (2012) proposed that altering distinct subprograms of MYC transcription, such as by SAE2 inactivation, may be a therapeutic strategy in MYC-driven cancers.
E1 enzymes activate ubiquitin and ubiquitin-like proteins, such as SUMO, in 2 steps by C-terminal adenylation and thioester bond formation to a conserved catalytic cysteine in the E1.Olsen et al. (2010) reported the crystal structures of the SUMO E1, a dimer of SAE2 and UBA2, in complex with SUMO adenylate and tetrahedral intermediate analogs at 2.45- and 2.6-angstrom resolution, respectively. They found that the switch between the 2 half-reactions was accompanied by a 130-degree rotation of the cys domain of UBA2 and remodeling of key structural elements that displaced side chains required for adenylation with side chains required for thioester bond formation.
In a 2.5-year-old girl with aplasia cutis congenita and ectrodactyly skeletal syndrome (ACCES;619959) manifest as scalp defects, high forehead, hip dysplasia, and fifth-finger clinodactyly,Marble et al. (2017) identified a de novo missense mutation in the UBA2 gene (G24V;613295.0001). The variant occurred at a highly conserved residue and was not found in public variant databases.
By whole-exome sequencing in a cohort of 7 Japanese families with syndromic or nonsyndromic split-hand/foot malformation (SHFM; see183600), who were negative for mutation in known genes or CNVs,Yamoto et al. (2019) identified a male proband with bilateral ectrodactyly of the hands and feet as well as bilateral tibial deficiency and undermasculinized genitalia, who was heterozygous for a de novo 1-bp duplication in the UBA2 gene (c.1324dupT;613295.0002). The duplication was not found in an in-house database of 218 exomes or in public variant databases.
In a 4-year-old boy with aplasia cutis congenita (ACC), ectrodactyly, tracheoesophageal fistula, and horseshoe kidney,Wang et al. (2020) identified heterozygosity for a 1-bp deletion in the UBA2 gene (c.327delT;613295.0003). His mother, who had isolated ACC, was also heterozygous for the deletion, which was not found in public variant databases.
In an 8-year-old boy with ectrodactyly of the feet, failure to thrive in infancy, and impaired intellectual development,Aerden et al. (2020) identified a de novo heterozygous 1-bp deletion in the UBA2 gene (c.612delA;613295.0004).
Using GeneDx and GeneMatcher,Schnur et al. (2021) ascertained 16 patients from 7 families with ACC and/or ectodermal dysplasia who were heterozygous for frameshift, nonsense, or missense mutations in the UB2 gene (see, e.g.,613295.0005-613295.0008). The authors noted that reported human UBA2 variants were distributed across the gene. In experiments with uba2-null zebrafish, injection with human UBA2 encoding missense variants failed to rescue the uba2 -/- phenotypes, in contrast to wildtype UBA2, and the authors concluded that the mostly likely mechanism of disease associated with UBA2 missense variants is loss of function. Given the highly variable expressivity of the human UBA2 phenotype, even within the same family, the authors suggested that there were likely other modifiers still to be identified.
By genome sequencing in a cohort of 69 patients with congenital limb malformations and no molecular diagnosis after standard clinical genetic testing,Elsner et al. (2021) identified 2 unrelated male patients with isolated bilateral split-hand malformations and heterozygous frameshift mutations in the UBA2 gene, one that occurred de novo and the other inherited from an apparently unaffected mother. Limited clinical information was reported. Subsequent Sanger sequencing of the UBA2 gene in 24 unrelated families with ectrodactyly yielded a man with unilateral split-hand malformation who was heterozygous for a UBA2 missense mutation (D50G). His daughter and her son were reported to be affected but were not available for testing. None of the mutations were found in public variant databases.
Using CRISPR/Cas9-targeted deletion,Schnur et al. (2021) generated uba2 knockout zebrafish lines. The survival rate of uba2 -/- zebrafish was significantly lower than wildtype or heterozygotes, with uba2-null zebrafish showing a mortality rate of approximately 50% at 8 dpf and 100% at 12 dpf. Nullizygous fish exhibited a wide phenotypic range, including abnormal pectoral fins that were short and upright-oriented, with collapsed and irregular fin-fold edges. Quantification of defects at 8 dpf showed abnormalities involving the pectoral fin in 100% of mutant fish, swim bladder in 94%, brain size in 91%, tail fin in 25%, and craniofacial structures in 9%. Immunohistochemistry revealed that compared to wildtype controls, uba2-null fish had small heads, reduced midbrain size, and low nuclei cell count with high accumulation of actin signal, implying a decreased proportion of gray to white matter. In addition, uba2 -/- fish had smaller eyes, reduced retinal thickness, retinal laminations, and lens defects. Abnormal craniofacial development included jaw malformations as well as malformed and hypoplastic ventral and dorsal cartilage structures with lack of basihyal and hypohyal development. In summary, the uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins, and the authors noted that total uba2 function loss recapitulated some tissue-level phenotypes and the variable expression observed in human UBA2-related phenotypes.
In a 2.5-year-old girl with scalp defects, high forehead, hip dysplasia, and fifth-finger clinodactyly (ACCES;619959),Marble et al. (2017) identified heterozygosity for a de novo G-to-T transversion (c.71G-T) in the UBA2 gene, resulting in a gly24-to-val (G24V) substitution at a highly conserved residue. The mutation was not found in her parents or in the NHLBI Exome Sequencing Project or ExAC databases.
Schnur et al. (2021) found that injection of uba2 -/- zebrafish, which recapitulated some features of human ACCES, with human UBA2 mRNA encoding G24V failed to rescue the phenotype, in contrast to wildtype human UBA2 mRNA, and thus the authors concluded that the most likely mechanism of G24V-associated disease was loss of function.
In a Japanese male proband (family 38) with bilateral ectrodactyly of the hands and feet, bilateral tibial deficiency, and undermasculinized genitalia (ACCES;619959),Yamoto et al. (2019) identified heterozygosity for a de novo 1-bp duplication (c.1324dupT, NM_005499.2) in the UBA2 gene, causing a frameshift predicted to result in a premature termination codon (Tyr442LeufsTer17). The duplication was not found in an in-house database of 218 exomes or in the gnomAD, HGVD, or 2KJPN databases.
In a 4-year-old boy with aplasia cutis congenita (ACC), ectrodactyly, tracheoesophageal fistula, and horseshoe kidney (ACCES;619959),Wang et al. (2020) identified heterozygosity for a 1-bp deletion (c.327delT) in exon 4 of the UBA2 gene, causing a frameshift predicted to result in a premature termination codon. His mother, who had isolated ACC, was also heterozygous for the deletion, which was not found in the DECIPHER, NHLBI Exome Sequencing Project, or ExAC databases.
In an 8-year-old boy with ectrodactyly of the feet, failure to thrive in infancy, and impaired intellectual development (ACCES;619959),Aerden et al. (2020) identified heterozygosity for a de novo 1-bp deletion (c.612delA, NM_005499.2) in the UBA2 gene, causing a frameshift predicted to result in a premature termination codon (Glu205LysfsTer63).
In a 4-generation family (family 1) with aplasia cutis congenita, microcephaly, and skeletal anomalies including ectrodactyly (ACCES;619959),Schnur et al. (2021) identified heterozygosity for a 2-bp deletion (c.816_817delAT, NM_005499) in exon 9 of the UBA2 gene, causing a frameshift predicted to result in a premature termination codon (Trp273AlafsTer13) within the catalytically active domain.
In a 3-generation family (family 3) with aplasia cutis congenita and microcephaly (ACCES;619959), originally described byMarble and Pridjian (2002),Schnur et al. (2021) identified heterozygosity for a c.364C-T transition (c.364C-T, NM_005499) in exon 5 of the UBA2 gene, resulting in an arg122-to-ter (R122X) substitution within the catalytically active domain.
In a 4-year-old boy from the Caribbean (family 7) with 4-limb ectrodactyly and global developmental delay (ACCES;619959),Schnur et al. (2021) identified heterozygosity for a de novo c.364C-G transversion (c.364C-G, NM_005499) in exon 5 of the UBA2 gene, resulting in an arg122-to-gly (R122G) substitution at a highly conserved residue within the catalytically active domain. The mutation was not found in the gnomAD database.Schnur et al. (2021) found that injection of uba2 -/- zebrafish, which recapitulated some features of human ACCES, with human UBA2 mRNA encoding R122G failed to rescue the phenotype, in contrast to wildtype human UBA2 mRNA, and thus the authors concluded that the most likely mechanism of R122G-associated disease was loss of function.
In a 4.75-year-old girl (family 5) with aplasia cutis congenita, severe developmental delay, and anteriorly placed anus (ACCES;619959),Schnur et al. (2021) identified heterozygosity for a de novo c.1447G-A transition (c.1447G-A, NM_005499) in exon 14 of the UBA2 gene, resulting in a glu483-to-lys (E483K) substitution at a highly conserved residue within the ubiquitin-like domain. The mutation was not found in the gnomAD database.Schnur et al. (2021) found that injection of uba2 -/- zebrafish, which recapitulated some features of human ACCES, with human UBA2 mRNA encoding E483K failed to rescue the phenotype, in contrast to wildtype human UBA2 mRNA, and thus the authors concluded that the most likely mechanism of E483K-associated disease was loss of function.
Aerden, M., Bauters, M., Van Den Bogaert, K., Vermeesch, J. R., Holvoet, M., Plasschaert, F., Devriendt, K.Genotype-phenotype correlations of UBA2 mutations in patients with ectrodactyly. Europ. J. Med. Genet. 63: 104009, 2020. [PubMed:32758660,related citations] [Full Text]
Azuma, Y., Tan, S.-H., Cavenagh, M. M., Ainsztein, A. M., Saitoh, H., Dasso, M.Expression and regulation of the mammalian SUMO-1 E1 enzyme. FASEB J. 15: 1825-1827, 2001. Note: Full Article Published Online June 18, 2001. [PubMed:11481243,related citations] [Full Text]
Desterro, J. M. P., Rodriguez, M. S., Kemp, G. D., Hay, R. T.Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J. Biol. Chem. 274: 10618-10624, 1999. [PubMed:10187858,related citations] [Full Text]
Elsner, J., Mensah, M. A., Holtgrewe, M., Hertzberg, J., Bigoni, S., Busche, A., Coutelier, M., de Silva, D. C., Elcioglu, N., Filges, I., Gerkes, E., Girisha, K. M., and 20 others.Genome sequencing in families with congenital limb malformations. Hum. Genet. 140: 1229-1239, 2021. [PubMed:34159400,images,related citations] [Full Text]
Gong, L., Li, B., Millas, S., Yeh, E. T. H.Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex. FEBS Lett. 448: 185-189, 1999. [PubMed:10217437,related citations] [Full Text]
Kessler, J. D., Kahle, K. T., Sun, T., Meerbrey, K. L., Schlabach, M. R., Schmitt, E. M., Skinner, S. O., Xu, Q., Li, M. Z., Hartman, Z. C., Rao, M., Yu, P., and 15 others.A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335: 348-353, 2012. [PubMed:22157079,images,related citations] [Full Text]
Marble, M., Guillen Sacoto, M. J., Chikarmane, R., Gargiulo, D., Juusola, J.Missense variant in UBA2 associated with aplasia cutis congenita, duane anomaly, hip dysplasia and other anomalies: A possible new disorder involving the SUMOylation pathway. Am. J. Med. Genet. 173A: 758-761, 2017. [PubMed:28110515,related citations] [Full Text]
Marble, M., Pridjian, G.Scalp defects, polythelia, microcephaly, and developmental delay: a new syndrome with apparent autosomal dominant inheritance. Am. J. Med. Genet. 108: 327-332, 2002. [PubMed:11920840,related citations] [Full Text]
Okuma, T., Honda, R., Ichikawa, G., Tsumagari, N., Yasuda, H.In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2. Biochem. Biophys. Res. Commun. 254: 693-698, 1999. [PubMed:9920803,related citations] [Full Text]
Olsen, S. K., Capili, A. D., Lu, X., Tan, D. S., Lima, C. D.Active site remodelling accompanies thioester bond formation in the SUMO E1. Nature 463: 906-912, 2010. [PubMed:20164921,images,related citations] [Full Text]
Schnur, R. E., Yousaf, S., Liu, J., Chung, W. K., Rhodes, L., Marble, M., Zambrano, R. M., Sobreira, N., Jayakar, P., Pierpont, M. E., Schultz, M. J., Pichurin, P. N., and 15 others.UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly. Genet. Med. 23: 1624-1635, 2021. [PubMed:34040189,images,related citations] [Full Text]
Wang, Y., Dupuis, L., Jobling, R., Kannu, P.Aplasia cutis congenita associated with a heterozygous loss-of-function UBA2 variant. Brit. J. Derm. 182: 792-794, 2020. [PubMed:31587267,related citations] [Full Text]
Yamoto, K., Saitsu, H., Nishimura, G., Kosaki, R., Takayama, S., Haga, N., Tonoki, H., Okumura, A., Horii, E., Okamoto, N., Suzumura, H., Ikegawa, S., Kato, F., Fujisawa, Y., Nagata, E., Takada, S., Fukami, M., Ogata, T.Comprehensive clinical and molecular studies in split-hand/foot malformation: identification of two plausible candidate genes (LRP6 and UBA2). Europ. J. Hum. Genet. 27: 1845-1857, 2019. [PubMed:31332306,images,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: UBA2
Cytogenetic location: 19q13.11 Genomic coordinates(GRCh38) : 19:34,428,381-34,471,251(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 19q13.11 | ACCES syndrome | 619959 | Autosomal dominant | 3 |
Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1; 601912), or sumoylation, regulates protein structure and intracellular localization. SAE1 (613294) and UBA2 form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins (Okuma et al., 1999).
By sequencing peptide fragments of the purified HeLa cell SUMO1-activating enzyme (SAE), followed by EST database analysis and RT-PCR, Desterro et al. (1999) cloned SAE1 and UBA2, which they called SAE2. The deduced SAE1 and SAE2 proteins contain 347 and 640 amino acids, respectively. SAE1 shares sequence similarity with the N terminus of ubiquitin-activating E1 enzymes (see UBE1; 314370), and SAE2 share sequence similarity with the C terminus of E1 enzymes. Both SAE subunits contain a conserved nucleotide-binding motif, and SAE2 contains an E1-like active-site cysteine. SAE2 has a calculated molecular mass of 72 kD. It had an apparent molecular mass of 90 kD by SDS-PAGE.
By searching an EST database for sequences similar to the ATP-binding region of UBE1, followed by RACE of a placenta cDNA library, Gong et al. (1999) cloned UBA2. UBA2 contains 2 ATG translation initiation codons. SDS-PAGE detected UBA2 at apparent molecular masses of 72 and 62 kD, suggesting usage of both ATG codons.
By searching an EST database for sequences similar to yeast Aos1 and Uba2, followed by screening a HeLa cell cDNA library, Okuma et al. (1999) cloned human SUA1 (SAE1) and UBA2, respectively.
Using Northern blot analysis, Azuma et al. (2001) detected both Aos1 and Uba2 in all adult mouse tissues examined, as well as in mouse embryos. Immunofluorescence analysis of HeLa cells showed AOS1 and UBA2 distributed throughout nuclei, but they were excluded from nucleoli. AOS1 and UBA2 copurified through a number of chromatography steps, suggesting they form a tight complex.
By whole-mount in situ hybridization in zebrafish, Schnur et al. (2021) detected uba2 transcript on the dorsoventral axis of 5-somite stage embryos. At later stages, uba2 was expressed in developing brain, eye, craniofacial structures, and fins. At 24 hours postfertilization (hpf), uba2 expression was restricted to the head region, including the eye and nervous system. At 35 hpf, prominent signal was observed in pectoral fins, whereas at later stages uba2 mRNA signal localized to the head region, specifically brain, neural retina, and lens. The authors noted that zebrafish uba2 is expressed in some structures analogous to those affected in humans harboring deleterious UBA2 variants (see MOLECULAR GENETICS).
By genomic sequence analysis, Gong et al. (1999) mapped the UBA2 gene to chromosome 19q12.
Schnur et al. (2021) stated that the UBA2 gene maps to chromosome 19q13.11.
Desterro et al. (1999) showed that purified SAE from HeLa cells bound to immobilized SUMO1 in the presence of ATP. Use of in vitro transcribed and translated SAE1 and SAE2 showed that SUMO1 binding required both SAE subunits and involved a direct thioester linkage between cys173 of SAE2 and SUMO1. Both SAE1 and SAE2 were required to transfer SUMO1 to the SUMO1-conjugating enzyme UBC9 (UBE2I; 601661). In the presence of SAE1, SAE2, UBC9, and ATP, SUMO1 was conjugated to recombinant I-kappa-B-alpha (NFKBIA; 164008). Desterro et al. (1999) concluded that the SAE1/SAE2 dimer functions in SUMO1 activation in a manner analogous to the single E1 ubiquitin-activating enzymes.
Gong et al. (1999) showed that in vitro-translated human UBA2 could precipitate with epitope-tagged sentrin-1 (SUMO1), ubiquitin (see 191339), and NEDD8 (603171) in the presence or absence of ATP. However, conjugation was only detected between UBA2 and sentrin-1, and this occurred only in the presence of AOS1. Sentrin-2 (SUMO2; 603042) and sentrin-3 (SUMO3; 602231) could also conjugate to UBA2 in the presence of AOS1.
The sumoylated form of RANGAP1 (602362) associates with the nuclear pore complex and is required for import of proteins into the nucleus. Okuma et al. (1999) showed that SUA1, UBA2, and UBC9 catalyzed in vitro sumoylation of RANGAP1. Faint RANGAP1 modification was observed in the absence of UBC9. Okuma et al. (1999) concluded that, in contrast to the 3-step ubiquitination reaction, which requires an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase, sumoylation is a 2-step reaction in which the SUA1/UBA2 dimer functions as an E1 enzyme and UBC9 functions as an E2 enzyme.
By screening for short hairpin RNAs (shRNAs) that altered the fitness of mammary epithelial cells only in the presence of aberrant MYC (190080) signaling, Kessler et al. (2012) identified SAE1 and SAE2 as MYC-synthetic lethal genes. Inactivation of SAE2 led to mitotic catastrophe and cell death upon MYC hyperactivation. SAE2 inhibition switched a MYC transcriptional subprogram from activated to repressed. A subset of sumoylation-dependent MYC switchers (SMS genes), including CASC5 (609173), BARD1 (601593), and CDC20 (603618), was required for mitotic spindle function and to support the MYC oncogenic program. Sae2 was required for growth of Myc-dependent tumors in mice. Transduction of MYC-dependent breast cancer cells with inducible SAE2 shRNA suggested that SAE2 was required for growth and fitness of these cell lines. Gene expression analysis of human breast cancers with hyperactive MYC suggested that low expression of SAE1 and SAE2 resulted in better metastasis-free survival. Kessler et al. (2012) proposed that altering distinct subprograms of MYC transcription, such as by SAE2 inactivation, may be a therapeutic strategy in MYC-driven cancers.
E1 enzymes activate ubiquitin and ubiquitin-like proteins, such as SUMO, in 2 steps by C-terminal adenylation and thioester bond formation to a conserved catalytic cysteine in the E1. Olsen et al. (2010) reported the crystal structures of the SUMO E1, a dimer of SAE2 and UBA2, in complex with SUMO adenylate and tetrahedral intermediate analogs at 2.45- and 2.6-angstrom resolution, respectively. They found that the switch between the 2 half-reactions was accompanied by a 130-degree rotation of the cys domain of UBA2 and remodeling of key structural elements that displaced side chains required for adenylation with side chains required for thioester bond formation.
In a 2.5-year-old girl with aplasia cutis congenita and ectrodactyly skeletal syndrome (ACCES; 619959) manifest as scalp defects, high forehead, hip dysplasia, and fifth-finger clinodactyly, Marble et al. (2017) identified a de novo missense mutation in the UBA2 gene (G24V; 613295.0001). The variant occurred at a highly conserved residue and was not found in public variant databases.
By whole-exome sequencing in a cohort of 7 Japanese families with syndromic or nonsyndromic split-hand/foot malformation (SHFM; see 183600), who were negative for mutation in known genes or CNVs, Yamoto et al. (2019) identified a male proband with bilateral ectrodactyly of the hands and feet as well as bilateral tibial deficiency and undermasculinized genitalia, who was heterozygous for a de novo 1-bp duplication in the UBA2 gene (c.1324dupT; 613295.0002). The duplication was not found in an in-house database of 218 exomes or in public variant databases.
In a 4-year-old boy with aplasia cutis congenita (ACC), ectrodactyly, tracheoesophageal fistula, and horseshoe kidney, Wang et al. (2020) identified heterozygosity for a 1-bp deletion in the UBA2 gene (c.327delT; 613295.0003). His mother, who had isolated ACC, was also heterozygous for the deletion, which was not found in public variant databases.
In an 8-year-old boy with ectrodactyly of the feet, failure to thrive in infancy, and impaired intellectual development, Aerden et al. (2020) identified a de novo heterozygous 1-bp deletion in the UBA2 gene (c.612delA; 613295.0004).
Using GeneDx and GeneMatcher, Schnur et al. (2021) ascertained 16 patients from 7 families with ACC and/or ectodermal dysplasia who were heterozygous for frameshift, nonsense, or missense mutations in the UB2 gene (see, e.g., 613295.0005-613295.0008). The authors noted that reported human UBA2 variants were distributed across the gene. In experiments with uba2-null zebrafish, injection with human UBA2 encoding missense variants failed to rescue the uba2 -/- phenotypes, in contrast to wildtype UBA2, and the authors concluded that the mostly likely mechanism of disease associated with UBA2 missense variants is loss of function. Given the highly variable expressivity of the human UBA2 phenotype, even within the same family, the authors suggested that there were likely other modifiers still to be identified.
By genome sequencing in a cohort of 69 patients with congenital limb malformations and no molecular diagnosis after standard clinical genetic testing, Elsner et al. (2021) identified 2 unrelated male patients with isolated bilateral split-hand malformations and heterozygous frameshift mutations in the UBA2 gene, one that occurred de novo and the other inherited from an apparently unaffected mother. Limited clinical information was reported. Subsequent Sanger sequencing of the UBA2 gene in 24 unrelated families with ectrodactyly yielded a man with unilateral split-hand malformation who was heterozygous for a UBA2 missense mutation (D50G). His daughter and her son were reported to be affected but were not available for testing. None of the mutations were found in public variant databases.
Using CRISPR/Cas9-targeted deletion, Schnur et al. (2021) generated uba2 knockout zebrafish lines. The survival rate of uba2 -/- zebrafish was significantly lower than wildtype or heterozygotes, with uba2-null zebrafish showing a mortality rate of approximately 50% at 8 dpf and 100% at 12 dpf. Nullizygous fish exhibited a wide phenotypic range, including abnormal pectoral fins that were short and upright-oriented, with collapsed and irregular fin-fold edges. Quantification of defects at 8 dpf showed abnormalities involving the pectoral fin in 100% of mutant fish, swim bladder in 94%, brain size in 91%, tail fin in 25%, and craniofacial structures in 9%. Immunohistochemistry revealed that compared to wildtype controls, uba2-null fish had small heads, reduced midbrain size, and low nuclei cell count with high accumulation of actin signal, implying a decreased proportion of gray to white matter. In addition, uba2 -/- fish had smaller eyes, reduced retinal thickness, retinal laminations, and lens defects. Abnormal craniofacial development included jaw malformations as well as malformed and hypoplastic ventral and dorsal cartilage structures with lack of basihyal and hypohyal development. In summary, the uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins, and the authors noted that total uba2 function loss recapitulated some tissue-level phenotypes and the variable expression observed in human UBA2-related phenotypes.
In a 2.5-year-old girl with scalp defects, high forehead, hip dysplasia, and fifth-finger clinodactyly (ACCES; 619959), Marble et al. (2017) identified heterozygosity for a de novo G-to-T transversion (c.71G-T) in the UBA2 gene, resulting in a gly24-to-val (G24V) substitution at a highly conserved residue. The mutation was not found in her parents or in the NHLBI Exome Sequencing Project or ExAC databases.
Schnur et al. (2021) found that injection of uba2 -/- zebrafish, which recapitulated some features of human ACCES, with human UBA2 mRNA encoding G24V failed to rescue the phenotype, in contrast to wildtype human UBA2 mRNA, and thus the authors concluded that the most likely mechanism of G24V-associated disease was loss of function.
In a Japanese male proband (family 38) with bilateral ectrodactyly of the hands and feet, bilateral tibial deficiency, and undermasculinized genitalia (ACCES; 619959), Yamoto et al. (2019) identified heterozygosity for a de novo 1-bp duplication (c.1324dupT, NM_005499.2) in the UBA2 gene, causing a frameshift predicted to result in a premature termination codon (Tyr442LeufsTer17). The duplication was not found in an in-house database of 218 exomes or in the gnomAD, HGVD, or 2KJPN databases.
In a 4-year-old boy with aplasia cutis congenita (ACC), ectrodactyly, tracheoesophageal fistula, and horseshoe kidney (ACCES; 619959), Wang et al. (2020) identified heterozygosity for a 1-bp deletion (c.327delT) in exon 4 of the UBA2 gene, causing a frameshift predicted to result in a premature termination codon. His mother, who had isolated ACC, was also heterozygous for the deletion, which was not found in the DECIPHER, NHLBI Exome Sequencing Project, or ExAC databases.
In an 8-year-old boy with ectrodactyly of the feet, failure to thrive in infancy, and impaired intellectual development (ACCES; 619959), Aerden et al. (2020) identified heterozygosity for a de novo 1-bp deletion (c.612delA, NM_005499.2) in the UBA2 gene, causing a frameshift predicted to result in a premature termination codon (Glu205LysfsTer63).
In a 4-generation family (family 1) with aplasia cutis congenita, microcephaly, and skeletal anomalies including ectrodactyly (ACCES; 619959), Schnur et al. (2021) identified heterozygosity for a 2-bp deletion (c.816_817delAT, NM_005499) in exon 9 of the UBA2 gene, causing a frameshift predicted to result in a premature termination codon (Trp273AlafsTer13) within the catalytically active domain.
In a 3-generation family (family 3) with aplasia cutis congenita and microcephaly (ACCES; 619959), originally described by Marble and Pridjian (2002), Schnur et al. (2021) identified heterozygosity for a c.364C-T transition (c.364C-T, NM_005499) in exon 5 of the UBA2 gene, resulting in an arg122-to-ter (R122X) substitution within the catalytically active domain.
In a 4-year-old boy from the Caribbean (family 7) with 4-limb ectrodactyly and global developmental delay (ACCES; 619959), Schnur et al. (2021) identified heterozygosity for a de novo c.364C-G transversion (c.364C-G, NM_005499) in exon 5 of the UBA2 gene, resulting in an arg122-to-gly (R122G) substitution at a highly conserved residue within the catalytically active domain. The mutation was not found in the gnomAD database. Schnur et al. (2021) found that injection of uba2 -/- zebrafish, which recapitulated some features of human ACCES, with human UBA2 mRNA encoding R122G failed to rescue the phenotype, in contrast to wildtype human UBA2 mRNA, and thus the authors concluded that the most likely mechanism of R122G-associated disease was loss of function.
In a 4.75-year-old girl (family 5) with aplasia cutis congenita, severe developmental delay, and anteriorly placed anus (ACCES; 619959), Schnur et al. (2021) identified heterozygosity for a de novo c.1447G-A transition (c.1447G-A, NM_005499) in exon 14 of the UBA2 gene, resulting in a glu483-to-lys (E483K) substitution at a highly conserved residue within the ubiquitin-like domain. The mutation was not found in the gnomAD database. Schnur et al. (2021) found that injection of uba2 -/- zebrafish, which recapitulated some features of human ACCES, with human UBA2 mRNA encoding E483K failed to rescue the phenotype, in contrast to wildtype human UBA2 mRNA, and thus the authors concluded that the most likely mechanism of E483K-associated disease was loss of function.
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