Alternative titles; symbols
HGNC Approved Gene Symbol: PSMB4
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:151,399,573-151,401,937 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | ?Proteasome-associated autoinflammatory syndrome 3 and digenic forms | 617591 | Autosomal recessive | 3 |
PSMB4 is a beta subunit of the human 26S proteasome (Gerards et al., 1994).
Gerards et al. (1994) cloned PSMB4 from a human lymphoma cDNA library. The deduced full-length 233-amino acid protein has a calculated molecular mass of 26 kD. Cleavage of the N terminus results in a mature protein of 220 amino acids with a calculated molecular mass of 24.5 kD. Western blot analysis following exogenic expression of PSMB4 in E. coli detected a soluble 27-kD protein, indicating that PSMB4 is present as a monomer.
McCusker et al. (1997) mapped the PSMB4 gene to chromosome 1q21 by fluorescence in situ hybridization.
Using real-time quantitative PCR and immunochemical analysis, Mairinger et al. (2014) found that PSMB4 mRNA expression was significantly upregulated and differently expressed among all subtypes of pulmonary neuroendocrine tumors. PSMB4 had the highest expression and greatest range in large-cell neuroendocrine carcinoma and was significantly associated with proliferative activity.
Using quantitative RT-PCR, Zhang et al. (2017) found significantly increased expression of PSMB4 mRNA in melanoma tissues and cell lines compared with normal skin. PSMB4 knockdown resulted in reduced proliferation of A375 melanoma cells in vitro. Inoculation of A375 melanoma cells in mice showed that disruption of PSMB4 reduced tumor growth compared with controls. The authors showed that microRNA-148B (MIR148B; 613787) regulated PSMB4 expression in melanoma cells by binding to its 3-prime UTR and thereby suppressed tumor growth. Enforced expression of MIR148B resulted inhibited growth of melanoma cells in vitro, and this inhibition was abolished by enforced expression of PSMB4.
In an 8-year-old Caucasian boy of American descent (patient 1) with proteasome-associated autoinflammatory syndrome-3 (PRAAS3; 617591), Brehm et al. (2015) identified compound heterozygous mutations in the PSMB4 gene (602177.0001 and 602177.0002). Patients from 2 unrelated families (families 4 and 5) with a similar disorder were found to have a heterozygous mutation in the PSMB4 gene (602177.0003 and 602177.0004) on 1 allele and a heterozygous mutation in either the PSMB9 (177045.0001) or PSMB8 (177046.0005) gene on the other allele, indicating digenic inheritance. The mutations, which were found by a combination of whole-exome sequencing and sequencing of proteasome candidate genes, were confirmed by Sanger sequencing, and segregated with the disorder in the families. Detailed functional studies, including in vitro studies of patient cells, expression of the mutations into HeLa cells, and siRNA-mediated knockdown of the PSMB4, PSMB3, and PSMB9 genes, demonstrated that the mutations resulted in variable defects in proteasome 20S and 26S assembly and maturation, with accumulation of proteasome precursor complexes, as well as impaired proteolytic activity. The defects were associated with induction of a type I interferon response with strong expression of IFN-inducible genes and an increase in chemokines and cytokines. Brehm et al. (2015) concluded that mutations in proteasomal subunit genes adversely affect proteasomal function, leading to cell stress and the triggering of a type I IFN gene response, causing a vicious cycle of uncontrolled inflammation in both hematopoietic and nonhematopoietic cells.
In an 8-year-old Caucasian boy of American descent (patient 1) with proteasome-associated autoinflammatory syndrome-3 (PRAAS3; 617591), Brehm et al. (2015) identified compound heterozygous mutations in the PSMB4 gene: an in-frame 9-bp deletion (c.634_642del, NM_002796.2) in exon 5, predicted to result in the deletion of 3 residues (Asp212_Val214del), and a G-to-A transition (c.-9G-A; 602177.0002) in the 5-prime untranslated region. The mutations, which were found by a combination of whole-exome sequencing and sequencing of proteasome candidate genes, were confirmed by Sanger sequencing. The 9-bp deletion was not found in the ExAC, 1000 Genomes Project, or Exome Sequencing Project databases; the c.-9G-A variant was found at a low frequency in the ExAC database. Each unaffected parent was heterozygous for 1 of the mutations. The patient had previously been reported by Liu et al. (2012) as 'patient 6.' Analysis of patient cells showed that the c.-9G-A allele was expressed at lower levels than wildtype, but that the Asp212_Val214del allele was expressed similarly to normal.
For discussion of the G-to-A transition (c.-9G-A, NM_002796.2) in the 5-prime untranslated region of the PSMB4 gene that was found in compound heterozygous state in a patient with proteasome-associated autoinflammatory syndrome-3 (PRAAS3; 617591), Brehm et al. (2015), see 602177.0001.
In 2 sibs (patients 4 and 5), born of unrelated Jamaican parents (family 4) with digenic proteasome-associated autoinflammatory syndrome-3 (PRAAS3; 617591), Brehm et al. (2015) identified heterozygous mutations in 2 different genes. Both patients carried a 1-bp insertion (c.44_45insG, NM_002796.2) in the PSMB4 gene, predicted to result in a frameshift and premature termination (Pro16SerfsTer45), and a missense mutation in the PSMB9 gene (G165D; 177045.0001). The mutations were found by screening of proteasome candidate genes and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for 1 of the mutations. The variant was not found in the ExAC, 1000 Genomes Project, or Exome Sequencing Project databases. Patient cells showed decreased PSMB4 mRNA levels compared to controls, suggesting a loss-of-function effect.
In 2 brothers (patients 6 and 7), born of unrelated Irish parents (family 5) with digenic proteasome-associated autoinflammatory syndrome-1/3 (see 256040), Brehm et al. (2015) identified heterozygous mutations in 2 different genes. Both carried a heterozygous c.666C-A transversion (c.666C-A, NM_002796.2) in the PSMB4 gene, resulting in a tyr222-to-ter (Y222X) substitution, on one allele, and a missense mutation in the PSMB8 gene (K105Q; 177046.0005) on the other allele. The mutations were found by screening of proteasome candidate genes and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for 1 of the mutations. The Y222X variant was not found in the ExAC, 1000 Genomes Project, or Exome Sequencing Project databases. In vitro studies showed that the C-terminally truncated Y222X variant was expressed. Expression of both mutations resulted in poor maturation of the subunit and poor incorporation into the 20S and 26S proteasomes.
Brehm, A., Liu, Y., Sheikh, A., Marrero, B., Omoyinmi, E., Zhou, Q., Montealegre, G., Biancotto, A., Reinhardt, A., Almeida de Jesus, A., Pelletier, M., Tsai, W. L., and 31 others. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J. Clin. Invest. 125: 4196-4211, 2015. Note: Erratum: J. Clin. Invest. 126: 795 only, 2016. [PubMed: 26524591] [Full Text: https://doi.org/10.1172/JCI81260]
Gerards, W. L. H., Hop, F. W. H., Hendriks, I. L. A. M., Bloemendal, H. Cloning and expression of a human pro(tea)some beta-subunit cDNA: a homologue of the yeast PRE4-subunit essential for peptidylglutamyl-peptide hydrolase activity. FEBS Lett. 346: 151-155, 1994. [PubMed: 8013624] [Full Text: https://doi.org/10.1016/0014-5793(94)00454-4]
Liu, Y., Ramot, Y., Torrelo, A., Paller, A. S., Si, N., Babay, S., Kim, P. W., Sheikh, A., Lee, C.-C. R., Chen, Y., Vera, A., Zhang, X., Goldbach-Mansky, R., Zlotogorski, A. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 64: 895-907, 2012. [PubMed: 21953331] [Full Text: https://doi.org/10.1002/art.33368]
Mairinger, F. D., Walter, R. F. H., Theegarten, D., Hager, T., Vollbrecht, C., Christoph, D. C., Worm, K., Ting, S., Werner, R., Stamatis, G., Mairinger, T., Baba, H., Zarogoulidis, K., Huang, H., Li, Q., Tsakiridis, K., Zarogoulidis, P., Schmid, K. W., Wohlschlaeger, J. Gene expression analysis of the 26S proteasome subunit PSMB4 reveals significant upregulation, different expression and association with proliferation in human pulmonary neuroendocrine tumours. J. Cancer 5: 646-654, 2014. [PubMed: 25157275] [Full Text: https://doi.org/10.7150/jca.9955]
McCusker, D., Jones, T., Sheer, D., Trowsdale, J. Genetic relationships of the genes encoding the human proteasome beta subunits and the proteasome PA28 complex. Genomics 45: 362-367, 1997. [PubMed: 9344661] [Full Text: https://doi.org/10.1006/geno.1997.4948]
Zhang, X., Lin, D., Lin, Y., Chen, H., Zou, M., Zhong, S., Yi, X., Han, S. Proteasome beta-4 subunit contributes to the development of melanoma and is regulated by miR-148b. Tumour Biol. 39: 1010428317705767, 2017. Note: Electronic Article. [PubMed: 28656878] [Full Text: https://doi.org/10.1177/1010428317705767]