HGNC Approved Gene Symbol: UBE3B
SNOMEDCT: 722056009;
Cytogenetic location: 12q24.11 Genomic coordinates (GRCh38) : 12:109,477,634-109,547,829 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.11 | Kaufman oculocerebrofacial syndrome | 244450 | Autosomal recessive | 3 |
Ubiquitination requires the sequential action of 3 enzymes: an activating enzyme (E1), a conjugating enzyme (E2), and a ligase (E3). UBE3B belongs to a class of monomeric ubiquitin ligases that contain a 350-amino acid HECT domain within their active site (Gong et al., 2003).
Using mouse Ube3b as probe, Gong et al. (2003) cloned UBE3B from a human cDNA library. The deduced 1,068-amino acid protein has a calculated molecular mass of about 123 kD, and the UBE3B transcript contains a 1.9-kb 3-prime untranslated region. Both mouse and human UBE3B contain an N-terminal IQ domain and a C-terminal HECT domain. Gong et al. (2003) determined that the transcript encoding the 1,068-amino acid protein lacks exon 20. A splice variant that includes exon 20 introduces a stop codon and encodes a deduced 708-amino acid protein with a calculated molecular mass of about 82 kD. This variant lacks the HECT domain. Gong et al. (2003) also detected splice variants that introduce changes to the 5-prime end of UBE3B. Mouse and human UBE3B share 92% amino acid identity overall and 99% identity in the HECT domain. Homologous sequences were identified in chick (97% amino acid identity) and in lower organisms, including plant. Northern blot analysis detected a transcript of about 5 kb in all mouse tissues examined. Highest levels were detected in brain, heart, and skeletal muscle, and these tissues also showed faint bands of 7.5 and 8.8 kb. RT-PCR detected a transcript lacking exon 20 in all human tissues examined, and a transcript containing exon 20 was detected in most tissues. RT-PCR of mouse and chick tissues detected only transcripts corresponding to the human transcript lacking exon 20.
By in situ hybridization in embryonic and postnatal mouse tissues, Basel-Vanagaite et al. (2012) found predominant expression of Ube3b in distinct anatomical structures of the developing central nervous system and in craniofacial structures.
Gong et al. (2003) determined that the mouse and human UBE3B genes contain 29 exons.
By genomic sequence analysis, Gong et al. (2003) mapped the UBE3B gene to chromosome 12q21.1-q23. They mapped the mouse Ube3b gene to a region of chromosome 5 that shows homology of synteny to human chromosome 12q21.1-q23.
Basel-Vanagaite et al. (2012) demonstrated that the probable C. elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and may be required under oxidative stress conditions.
Basel-Vanagaite et al. (2012) performed exome sequencing of 2 unrelated individuals with Kaufman oculocerebrofacial syndrome (KOS; 244450), which the authors called blepharophimosis-ptosis intellectual disability syndrome (BPIDS), and identified the UBE3B gene as the only gene with rare or unique biallelic damaging variants in both individuals. Individual 1 had a homozygous splice site mutation (c.1741+2T-C; 608047.0001), which was present in heterozygous state in her unaffected first-cousin parents. Individual 2 and her affected brother, who were previously reported by Dentici et al. (2011), had a maternally inherited deletion (c.2223_2224delAG; 608047.0002) and a paternally inherited splice site mutation (c.545-2AG; 608047.0003). By sequencing the coding exons of the UBE3B gene in a fourth affected individual, Basel-Vanagaite et al. (2012) detected another homozygous mutation (E727P; 608047.0004), which was present in heterozygous state in the patient's unaffected first-cousin parents. None of the mutations were present in 100 ethnically matched control individuals or in the NHLBI Exome Sequencing Project database.
Basel-Vanagaite et al. (2014) reported 6 patients from 5 unrelated families with KOS and homozygous or compound heterozygous mutation in the UBE3B gene. They identified homozygous missense mutations in cis outside the HECT domain (608047.0005) in a patient with mildly dysmorphic facial features, a homozygous missense mutation (G779R; 608047.0006) in sibs previously diagnosed with Toriello-Carey syndrome (217980), and compound heterozygosity (608047.0007; 608047.0008) in a patient previously reported as having a possibly novel disorder. Basel-Vanagaite et al. (2014) stated that their findings brought the number of reported KOS patients to 12 and expanded the clinical and mutational spectrum of the disorder.
Basel-Vanagaite et al. (2012) confirmed by quantitative PCR that Ube3b knockdown mice do not express detectable levels of Ube3b mRNA. Ube3b -/- mice had severely reduced body weight, small body size, and reduced brain section area with reduced size of the hippocampus and dentate gyrus, reduced grip strength, reduced low-density lipoprotein levels and a trend toward reduced total and HDL cholesterol levels, mild hearing impairment, and acute inflammation, calcification, and dilated lymphovascular channels of the cornea. Basel-Vanagaite et al. (2012) suggested that Ube3b -/- mice are a model of the UBE3B-deficient Kaufman oculocerebrofacial syndrome in anomalies of body and brain size, weight, muscular strength, and cholesterol levels.
In a girl with Kaufman oculocerebrofacial syndrome (KOS; 244450) who was born to unaffected first-cousin parents of Israeli Arab origin, Basel-Vanagaite et al. (2012) identified a homozygous variant (c.1741+2T-C) affecting the consensus splice donor site of exon 16 in the UBE3B gene. The mutation led to skipping of exon 16 and, to a lesser extent, skipping of exons 16 and 17 in RNA derived from blood of the patient. The parents were heterozygous carriers of the mutation, which was not found in 100 ethnically matched controls or in the NHLBI Exome Sequencing Project database. The mutation introduces a premature termination codon and is thus expected to result in nonsense-mediated mRNA decay and/or protein truncation. The authors called the disorder blepharophimosis-ptosis-intellectual disability syndrome.
In an Italian sister and brother with Kaufman oculocerebrofacial syndrome (KOS; 244450), originally reported by Dentici et al. (2011), Basel-Vanagaite et al. (2012) identified compound heterozygous mutations in the UBE3B gene: a maternally inherited 2-bp deletion (c.2223_2224delAG; Arg741SerfsTer3) and a paternally inherited splice acceptor mutation (c.545-2A-G; 608047.0003). The splice site mutation caused skipping of exon 8 and skipping of exons 8 and 9 in RNA derived from the sister's blood. Both variants introduce premature termination codons and are thus expected to result in nonsense-mediated mRNA decay and/or protein truncation. The mutations were not found in 100 ethnically matched controls or in the NHLBI Exome Sequencing Project database. The authors called the disorder blepharophimosis-ptosis-intellectual disability syndrome.
For discussion of the splice site mutation in the UBE3B gene (c.545-2A-G) that was found in compound heterozygous state in patients with Kaufman oculocerebrofacial syndrome (KOS; 244450) by Basel-Vanagaite et al. (2012), see 608047.0002.
By sequencing the coding exons of the UBE3B gene in a girl with Kaufman oculocerebrofacial syndrome (KOS; 244450) who was born to unaffected first-cousin parents of Tunisian origin, Basel-Vanagaite et al. (2012) identified a homozygous c.2180A-C mutation that was predicted to lead to a glu727-to-pro (Q727P) substitution at a highly conserved residue in the HECT domain. Both parents were heterozygous carriers of the mutation, which was not found in 100 ethnically matched controls or in the NHLBI Exome Sequencing Project database. The mutation was located within a 35-Mb region of homozygosity in the proband, as shown by genomewide SNP array genotyping, consistent with a large region of homozygosity-by-descent. The authors called the disorder blepharophimosis-ptosis-intellectual disability syndrome.
In a 7-year-old Turkish boy (patient 2), the child of unaffected first cousins, with Kaufman oculocerebrofacial syndrome (KOS; 244450), Basel-Vanagaite et al. (2014) identified homozygosity for 2 missense mutations in cis in the UBE3B gene, a c.1445T-A transversion (c.1445T-A, GRCh37) resulting in a leu482-to-his (L482H) substitution, and a c.1616T-C transition (c.1616T-C, GRCh37) resulting in a leu539-to-pro (L539P) substitution. Each parent was heterozygous for both mutations. Both mutations occurred outside the HECT domain, L482H in the leucine-rich region and L539P in a predicted coiled-coil domain. The mutations were identified by whole-exome sequencing and were absent from the Exome Variant Server and 376 Turkish control alleles. The patient had mild and atypical facial dysmorphism.
In a brother and sister (patients 4 and 5) of Mexican origin with Kaufman oculocerebrofacial syndrome (KOS; 244450), Basel-Vanagaite et al. (2014) identified a homozygous c.2335G-A transition (c.2335G-A, GRCh37) in the UBE3B gene that resulted in a gly779-to-arg (G779R) substitution at a conserved residue in the HECT domain of the protein. The mutation was identified by exon sequencing of the UBE3B gene and was not present in the Exome Variant Server. The patients had been reported by Toriello et al. (2003) with a diagnosis of Toriello-Carey syndrome (217980). The presence of suggestive facial features led Basel-Vanagaite et al. (2014) to sequence the UBE3B gene in these patients; sequencing of 4 additional Toriello-Carey syndrome patients who did not have a facial appearance characteristic of KOS detected no UBE3B mutations.
In a 25-year-old German man (patient 6) with Kaufman oculocerebrofacial syndrome (KOS; 244450), Basel-Vanagaite et al. (2014) detected compound heterozygosity for mutations in the UBE3B gene: a c.2098C-T transition (c.2098C-T, GRCh37) resulting in a gln700-to-ter (Q700X) substitution, and a c.2990G-C transversion resulting in an arg997-to-pro (R997P) substitution. The Q700X mutation, inherited from the mother, truncated the protein N-terminal to the HECT domain. The R997P mutation, present in the unaffected brother and likely inherited from the deceased father, occurred in the HECT domain. The mutations were detected by exome sequencing and were absent from the Exome Variant Server. The patient had been reported as an infant by Buntinx and Majewski (1990) as having a possibly novel phenotype.
For discussion of the c.2990G-C transversion (c.2990G-C, GRCh37) in the UBE3B gene, resulting in an arg997-to-pro (R997P) substitution, that was found in compound heterozygous state in a patient with Kaufman oculocerebrofacial syndrome (KOS; 244450) by Basel-Vanagaite et al. (2014), see 608047.0007.
Basel-Vanagaite, L., Dallapiccola, B., Ramirez-Solis, R., Segref, A., thiele, H., Edwards, A., Arends, M. J., Miro, X., White, J. K., Desir, J., Abramowicz, M., Dentici, M. L., and 24 others. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am. J. Hum. Genet. 91: 998-1010, 2012. [PubMed: 23200864] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.011]
Basel-Vanagaite, L., Yilmaz, R., Tang, S., Reuter, M. S., Rahner, N., Grange, D. K., Mortenson, M., Koty, P., Feenstra, H., Farwell Gonzalez, K. D., Sticht, H., Boddaert, N., Desir, J., Anyane-Yeboa, K., Zweier, C., Reis, A., Kubisch, C., Jewett, T., Zeng, W., Borck, G. Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations. Hum. Genet. 133: 939-949, 2014. [PubMed: 24615390] [Full Text: https://doi.org/10.1007/s00439-014-1436-2]
Buntinx, I., Majewski, F. Blepharophimosis, iris coloboma, microgenia, hearing loss, postaxial polydactyly, aplasia of corpus callosum, hydroureter, and developmental delay. Am. J. Med. Genet. 36: 273-274, 1990. [PubMed: 1694631] [Full Text: https://doi.org/10.1002/ajmg.1320360304]
Dentici, M. L., Mingarelli, R., Dallapiccola, B. The difficult nosology of blepharophimosis-mental retardation syndromes: report on two siblings. Am. J. Med. Genet. 155A: 459-465, 2011. [PubMed: 21567902] [Full Text: https://doi.org/10.1002/ajmg.a.33642]
Gong, T.-W. L., Huang, L., Warner, S. J., Lomax, M. I. Characterization of the human UBE3B gene: structure, expression, evolution, and alternative splicing. Genomics 82: 143-152, 2003. [PubMed: 12837265] [Full Text: https://doi.org/10.1016/s0888-7543(03)00111-3]
Toriello, H. V., Carey, J. C., Addor, M.-C., Allen, W., Burke, L., Chun, N., Dobyns, W., Elias, E., Gallagher, R., Hordijk, R., Hoyme, G., Irons, M., and 13 others. Toriello-Carey syndrome: delineation and review. Am. J. Med. Genet. 123A: 84-90, 2003. [PubMed: 14556252] [Full Text: https://doi.org/10.1002/ajmg.a.20493]