Alternative titles; symbols
HGNC Approved Gene Symbol: PSMB9
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:32,854,192-32,859,851 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.32 | Proteasome-associated autoinflammatory syndrome 6 | 620796 | Autosomal dominant | 3 |
The generation of peptides from cytosolic proteins for transport into the endoplasmic reticulum, where they associate with major histocompatibility complex (MHC) class I molecules, is thought to be a function of the proteasome. The proteasome is a large complex of subunits with multiple proteolytic activities. Two genes identified in the MHC class II region, TAP1 (170260) and TAP2 (170261), are thought to encode the peptide transport proteins. Glynne et al. (1991) reported a proteasome-related sequence, RING10 (LMP7; 177046), mapping between the 2 transporter genes. Kelly et al. (1991) described a second human proteasome-like gene, RING12, within 500 bp centromeric to the RING4 locus, with the 5-prime promoter ends of the 2 genes adjacent. Northern blot analysis detected a 900-bp mRNA transcript in both B and T lymphocytes. Expression of mRNA was strongly upregulated in epithelial and fibroblast cell lines by gamma-interferon (147570). Therefore, RING12, 4, 10, and 11 form a tightly linked cluster of interferon-inducible genes within the MHC with an essential role in antigen processing.
Zhou et al. (1993) found that the Lmp2 gene was expressed in most tissues of unstimulated mice, except for brain tissue.
Martinez and Monaco (1991) mapped the mouse Lmp2 gene to the MHC class II region of chromosome 17.
Zhou et al. (1993) found that the Lmp2 gene of the mouse has 6 exons and a genomic organization very similar to that of the human LMP2 gene.
Driscoll et al. (1993) showed that the MHC-linked LMP2 and LMP7 subunits function to amplify specific endopeptidase activities of the proteasome. Gaczynska et al. (1993) presented experiments suggesting that gamma-interferon and expression of the LMP2 and LMP7 genes should favor the production by proteasomes of the types of peptides found on MHC class I molecules, which terminate almost exclusively with hydrophobic or basic residues.
Deng et al. (1995) found evidence suggesting that LMP genes have effects on susceptibility to insulin-dependent diabetes mellitus (IDDM; 222100), independent of HLA-DR and HLA-DQ. A genomic polymorphism of LMP7 (177046) was found to be strongly associated with IDDM, and an arg/his-60 polymorphism in LMP2 was found to be associated with IDDM in subjects containing an HLA-DR4-DQB1*0302 haplotype.
Interferon-gamma (147570) treatment increases expression of LMP2 and LMP7 subunits of the proteasome and decreases expression of 2 proteasome subunits, named X (600306) and Y (600307), which alters the proteolytic specificity of proteasomes. From the cDNAs encoding X and Y, Akiyama et al. (1994) showed that their proteins have high amino acid similarity to LMP7 and LMP2, respectively. Interferon-gamma may induce subunit replacement of X and Y by LMP7 and LMP2, respectively, producing proteasomes that may be more appropriate for the immunologic processing of endogenous antigens.
During meiosis, the reductional segregation of homologous chromosomes at the first meiotic division requires reciprocal exchange (crossing over) between homologs. The number of crossovers is tightly regulated (1 to 2 per homolog in mice), and their distribution in the genome is not random--recombination 'hot' and 'cold' regions can be identified (Petes, 2001). Guillon and de Massy (2002) developed a molecular assay to study these exchange events directly in mouse germ cells. The analysis was developed in reference to the Psmb9 hotspot region on mouse chromosome 17. They showed that this hotspot is an initiation site of meiotic recombination on the basis of 2 observations: (1) crossover density is maximal in an interval of 210 bp and decreases on both sides of this region; and (2) a high frequency of gene conversion is found in the region of highest crossover density. They used this strategy to carry out the first temporal analysis of meiotic recombination in mouse spermatogenesis and demonstrated that crossover events occur during the pachytene stage of meiotic prophase.
Proteasome-Associated Autoinflammatory Syndrome 3, Digenic
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 missense mutation in the PSMB9 gene (G165D; 177045.0001) and a frameshift mutation in the PSMB4 gene (c.44_45insG; 602177.0003). 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. Functional studies of the G165D variant were not performed, but levels of PSMB4 were severely decreased in patient cells. Detailed functional studies, including in vitro studies of patient cells, expression of the mutations into HeLa cells, and siRNA-mediated knockdown of the proteasomal 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 the secretion of 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.
Proteasome-Associated Autoinflammatory Syndrome 6
In 2 unrelated patients with proteasome-associated autoinflammatory syndrome-6 (PRAAS6; 620796), Kanazawa et al. (2021) identified the same de novo heterozygous missense mutation in the PSMB9 gene (G156D; 177045.0002). The mutation was predicted to disrupt beta ring interactions necessary for proteasome formation. Analysis of immortalized B cells from patient 1 and interferon-gamma-stimulated fibroblasts from patient 2 showed diminished incorporation of subunits into the 20S proteasome complex and decreased 20S proteasome activity. 26S proteasome activity was normal in both patient cell lines.
Kataoka et al. (2021) identified de novo heterozygosity for the G156D mutation in the PSMB9 gene in a patient with PRAAS6. A proteasome assay in lymphoblastoid cells derived from the patient demonstrated loss of chymotrypsin-like, trypsin-like, and caspase-like protease activities. Expression of PSMB9 with the G156D mutation in A151 cells resulted in decreased protease activity, leading Kataoka et al. (2021) to conclude that the mutation had dominant-negative effects.
Van Kaer et al. (1994) generated healthy mice with disrupted Lmp2 genes. Proteasomal peptidase activity against hydrophobic and basic substrates but not acidic substrates was lower in spleen and liver from mutant mice compared with wildtype mice. Differences in muscle and brain were not significant. Although flow cytometric analysis showed no difference in MHC class I expression, antigen-presenting cells from mutant mice were less able to stimulate a T-cell hybridoma specific for a nucleoprotein (NP) envelope antigen of an influenza A virus. Mutant mice also had less than half of the wildtype levels of CD8 (see 186910)-positive T lymphocytes and generated much lower levels of cytotoxic T-cell precursors specific for NP, though not for ovalbumin. Van Kaer et al. (1994) concluded that LMP2 selectively influences antigen processing of MHC class I-restricted antigens.
Kanazawa et al. (2021) generated mice that had heterozygosity or homozygosity for a G156D mutation (177045.0002) in the Psmb9 gene. In interferon-gamma-stimulated embryonic fibroblasts from both the heterozygous and homozygous mutant mice, impaired incorporation of the beta1 subunit into the 20S proteasome complex was observed. The 20S complex activity was decreased in the embryonic fibroblasts of both mutant mice. In the heterozygous mutant mice, the thymus was small and the spleen had defective formation of follicles with a reduction of B and T cells and dendritic cells. Serum levels of all Ig isotypes were also reduced. Natural killer cells were normal, and neutrophils and monocytes were increased in spleen and bone marrow.
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 c.494G-A transition (c.494G-A, NM_002800.4) in the PSMB9 gene, resulting in a gly165-to-asp (G165D) substitution on 1 allele, and a 1-bp insertion in the PSMB4 gene (c.44_45insG; 602177.0003), predicted to result in a frameshift and premature termination (Pro16SerfsTer45) 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 G165D substitution occurred at a highly conserved residue in a loop interconnecting 2 alpha-helices that define the position of a caspase-like activity. Functional studies of the G165D variant were not performed, but levels of PSMB4 were severely decreased in patient cells.
In 2 unrelated patients with proteasome-associated autoinflammatory syndrome-6 (PRAAS6; 620796), Kanazawa et al. (2021) identified a de novo heterozygous c.467G-A transition (c.467G-A, NM_002800) in the PSMB9 gene, resulting in a gly156-to-asp (G156D) substitution. The mutation was identified by sequencing of a panel of genes related to ubiquitin proteasome-system, autophagy and interferonopathies and by whole-exome sequencing. The mutation was predicted to disrupt beta ring interactions necessary for proteasome formation. Analysis of immortalized B cells from patient 1 showed diminished incorporation of subunits into the 20S proteasome complex and decreased 20S proteasome activity.
In a patient with PRAAS6, Kataoka et al. (2021) identified de novo heterozygosity for the G156D mutation in the PSMB9 gene. The mutation was identified by whole-exome sequencing. A proteasome assay in lymphoblastoid cells derived from the patient demonstrated loss of chymotrypsin-like, trypsin-like, and caspase-like protease activity.
Akiyama, K., Yokota, K., Kagawa, S., Shimbara, N., Tamura, T., Akioka, H., Nothwang, H. G., Noda, C., Tanaka, K., Ichihara, A. cDNA cloning and interferon gamma down-regulation of proteasomal subunits X and Y. Science 265: 1231-1234, 1994. [PubMed: 8066462] [Full Text: https://doi.org/10.1126/science.8066462]
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]
Deng, G. Y., Muir, A., Maclaren, N. K., She, J.-X. Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies. Am. J. Hum. Genet. 56: 528-534, 1995. [PubMed: 7847389]
Driscoll, J., Brown, M. G., Finley, D., Monaco, J. J. MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature 365: 262-264, 1993. [PubMed: 8371781] [Full Text: https://doi.org/10.1038/365262a0]
Gaczynska, M., Rock, K. L., Goldberg, A. L. Gamma-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 365: 264-267, 1993. Note: Erratum: Nature 374: 290 only, 1995. [PubMed: 8396732] [Full Text: https://doi.org/10.1038/365264a0]
Glynne, R., Powis, S. H., Beck, S., Kelly, A., Kerr, L. A., Trowsdale, J. A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC. Nature 353: 357-360, 1991. [PubMed: 1922342] [Full Text: https://doi.org/10.1038/353357a0]
Guillon, H., de Massy, B. An initiation site for meiotic crossing-over and gene conversion in the mouse. Nature Genet. 32: 296-299, 2002. [PubMed: 12244318] [Full Text: https://doi.org/10.1038/ng990]
Kanazawa, N., Hemmi, H., Kinjo, N., Ohnishi, H., Hamazaki, J., Mishima, H., Kinoshita, A., Mizushima, T., Hamada, S., Hamada, K., Kawamoto, N., Kadowaki, S., and 20 others. Heterozygous missense variant of the proteasome subunit beta-type 9 causes neonatal-onset autoinflammation and immunodeficiency. Nature Commun. 12: 6819, 2021. [PubMed: 34819510] [Full Text: https://doi.org/10.1038/s41467-021-27085-y]
Kataoka, S., Kawashima, N., Okuno, Y., Muramatsu, H., Miwata, S., Narita, K., Hamada, M., Murakami, N., Taniguchi, R., Ichikawa, D., Kitazawa, H., Suzuki, K., and 13 others. Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor. J. Allergy Clin. Immun. 148: 639-644, 2021. [PubMed: 33727065] [Full Text: https://doi.org/10.1016/j.jaci.2021.03.010]
Kelly, A., Powis, S. H., Glynne, R., Radley, E., Beck, S., Trowsdale, J. Second proteasome-related gene in the human MHC class II region. Nature 353: 667-668, 1991. [PubMed: 1922385] [Full Text: https://doi.org/10.1038/353667a0]
Martinez, C. K., Monaco, J. J. Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene. Nature 353: 664-667, 1991. [PubMed: 1681432] [Full Text: https://doi.org/10.1038/353664a0]
Petes, T. D. Meiotic recombination hot spots and cold spots. Nature Rev. Genet. 2: 360-369, 2001. [PubMed: 11331902] [Full Text: https://doi.org/10.1038/35072078]
Van Kaer, L., Ashton-Rickardt, P. G., Eichelberger, M., Gaczynska, M., Nagashima, K., Rock, K. L., Goldberg, A. L., Doherty, P. C., Tonegawa, S. Altered peptidase and viral-specific T cell response in LMP2 mutant mice. Immunity 1: 533-541, 1994. [PubMed: 7600282] [Full Text: https://doi.org/10.1016/1074-7613(94)90043-4]
Zhou, P., Zanelli, E., Smart, M., David, C. Genomic organization and tissue expression of mouse proteasome gene Lmp-2. Genomics 16: 664-668, 1993. [PubMed: 8325639] [Full Text: https://doi.org/10.1006/geno.1993.1245]