Alternative titles; symbols
HGNC Approved Gene Symbol: PSMA3
Cytogenetic location: 14q23.1 Genomic coordinates (GRCh38): 14:58,244,843-58,272,004 (from NCBI)
The proteasome is a multicatalytic protease complex that catalyzes an energy-dependent, extralysosomal proteolytic pathway responsible for selective elimination of proteins with aberrant structures and naturally occurring short-lived proteins related to metabolic regulation and cell cycle progression. The proteasome has a sedimentation coefficient of 26S and is composed of a 20S catalytic core and a 22S regulatory complex. Eukaryotic 20S proteasomes have a molecular mass of 700 to 800 kD and consist of a set of over 15 kinds of polypeptides of 21 to 32 kD. All eukaryotic 20S proteasome subunits can be classified grossly into 2 subfamilies, alpha and beta, by their high similarity with either the alpha or beta subunits of the archaebacterium Thermoplasma acidophilum (summary by Akioka et al., 1995).
Akioka et al. (1995) cloned a gene encoding an alpha-type subunit, HC8, of the human 20S proteasome. They showed that its CAAT and TATA boxes function as promoters, in contrast to the promoters of the HC3 (PSMA2; 176842) and HC5 (PSMB1; 602017) genes.
By fluorescence in situ hybridization, Akioka et al. (1995) mapped the PSMA3 gene to 14q23, which differed from the chromosomal location of 9 other proteasomal subunit genes that had been mapped up to that time. In their Table 1, they listed the chromosomal localization of 4 alpha-type subunits and 5 beta-type subunits.
In 2 unrelated patients with digenic proteasome-associated autoinflammatory syndrome-1 (PRAAS1; 256040), Brehm et al. (2015) identified heterozygous mutations in 2 different genes. Both patients carried a heterozygous mutation in the PSMA3 gene (176843.0001 and 176843.0002) on 1 allele and a common heterozygous missense mutation in the PSMB8 gene (T75M; 177046.0001) on the other allele. The mutations were found by a combination of whole-exome sequencing and screening of proteasomal candidate genes. The mutations segregated with the disorder in the families, although 1 of the patients had a de novo mutation in the PSMA3 gene. The patients had previously been reported by Liu et al. (2012). 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 a 6-year-old boy (patient 2) of American/Caucasian descent with digenic proteasome-associated autoinflammatory syndrome-1 (PRAAS1; 256040), Brehm et al. (2015) identified heterozygous mutations in 2 different genes. He carried a de novo in-frame 3-bp deletion (c.696_698delAAG, NM_002788.3) in exon 10 of the PSMA3 gene, resulting in the deletion of conserved residue Arg233 (Arg233del) on 1 allele, and a paternally inherited heterozygous missense mutation in the PSMB8 gene (T75M; 177046.0001) on the other allele. The PSMA3 protein was not detectable in proteasomal complexes. The mutations were found by a combination of whole-exome sequencing and screening of proteasomal candidate genes. The PSMA3 mutation was not found in the ExAC database. The patient had previously been reported by Liu et al. (2012) as patient 7.
In a 5-year-old Spanish boy (patient 3) with digenic proteasome-associated autoinflammatory syndrome-1 (PRAAS1; 256040), Brehm et al. (2015) identified heterozygous mutations in 2 different genes. He carried a T-to-C transition in intron 5 of the PSMA3 gene (c.404+2T-C, NM_002788.3), resulting in a splice site alteration, a frameshift, and premature termination (His111PhefsTer10) on 1 allele, and a heterozygous missense mutation in the PSMB8 gene (T75M; 177046.0001) on the other allele. The mutations, which were found by a combination of whole-exome sequencing and screening of proteasomal candidate genes, segregated with the disorder in the family. The PSMA3 mutation was not found in the ExAC database. The patient had previously been reported by Liu et al. (2012) as patient 9.
Akioka, H., Forsberg, N. E., Ishida, N., Okumura, K., Nogami, M., Taguchi, H., Noda, C., Tanaka, K. Isolation and characterization of the HC8 subunit gene of the human proteasome. Biochem. Biophys. Res. Commun. 207: 318-323, 1995. [PubMed: 7857283] [Full Text: https://doi.org/10.1006/bbrc.1995.1190]
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]
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]