Online Mendelian Inheritance in Man (OMIM) (original) (raw)

Cytogenetic location: 14q32.11 Genomic coordinates (GRCh38) : 14:90,256,553-90,275,429 (from NCBI)

TEXT

Description

Ubiquitinated proteins are degraded by a 26S ATP-dependent protease. The protease is composed of a 20S catalytic proteasome and 2 PA700 regulatory modules. The PA700 complex is composed of multiple subunits, with at least 6 related ATPases, including PSMC1, and approximately 15 non-ATPase polypeptides. Each of the 6 ATPases, namely PSMC1, PSMC2 (154365), PSMC3 (186852), PSMC4 (602707), PSMC5 (601681), and PSMC6 (602708), contains an AAA (ATPases associated with diverse cellular activities) domain (summary by Tanahashi et al., 1998).

Cloning and Expression

Dubiel et al. (1992) cloned cDNAs encoding subunit 4 (S4) of the 26S protease by screening a HeLa cell cDNA library with probes that were produced using the protein sequence. The 440-amino acid protein has a molecular mass of 51 kD by SDS-PAGE.

Hoyle and Fisher (1996) found that the human and mouse PSMC1 proteins have 99% amino acid identity.

Gene Function

Spinocerebellar ataxia type 7 (SCA7; 164500) is a neurodegenerative disorder characterized by ataxia and selective neuronal cell loss caused by the expansion of a translated CAG repeat encoding a polyglutamine tract in ataxin-7, the SCA7 gene product. Matilla et al. (2001) used a 2-hybrid assay to show that ataxin-7 interacts with the ATPase subunit S4 of the 19S regulatory complex of the 26S proteasome. The ataxin-7/S4 association was modulated by the length of the polyglutamine tract, whereby S4 showed a stronger association with the wildtype allele of ataxin-7. Endogenous ataxin-7 localized to discrete nuclear foci that also contained additional components of the proteasomal complex. Immunohistochemical analyses suggested alterations either of the distribution or the levels of S4 immunoreactivity in neurons that degenerate in SCA7 brains. Immunoblot analyses demonstrated reduced levels of S4 in SCA7 cerebella without evident alterations in the levels of other proteasome subunits. The authors suggested a role for S4 and ubiquitin-mediated proteasomal proteolysis in the molecular pathogenesis of SCA7.

Mapping

By fluorescence in situ hybridization, Tanahashi et al. (1998) mapped the human PSMC1 gene to chromosome 19p13.3. However, Gross (2011) mapped the PSMC1 gene to chromosome 14q32.11 based on an alignment of the PSMC1 sequence (GenBank BT009826) with the genomic sequence (GRCh37).

By analysis of an interspecific backcross, Hoyle and Fisher (1996) mapped the mouse Psmc1 gene to chromosome 12.

Nomenclature

The PSMC1 gene product, which Dubiel et al. (1992) called subunit 4 (S4), is distinct from the PSMC4 (602707) gene product.

Molecular Genetics

In 3 brothers, born of consanguineous Bedouin parents, with Birk-Aharoni syndrome (BKAH; 620071), a neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss, Aharoni et al. (2022) identified a homozygous missense mutation in the PSMC1 gene (I328T; 602706.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including gnomAD. Expression of the mutation in Drosophila failed to fully rescue the ocular ommatidia defects in Rpt2 (Psmc1)-null flies, whereas wildtype was able to, demonstrating that the mutation causes a functional defect (see ANIMAL MODEL).

Animal Model

Aharoni et al. (2022) noted that tissue-specific knockdown of the Drosophila PSMC1 ortholog Rpt2 results in eye degeneration with severe depigmentation, necrosis, and ommatidia defects. While ocular depigmentation and necrosis were fully rescued in Rpt2-null flies by both wildtype human PSMC1 and I328T (602706.0001), other abnormalities of the ommatidia affected by Rpt2 silencing were fully rescued with wildtype PSMC1 but not with mutant PSMC1, indicating a functional defect.

ALLELIC VARIANTS 1 Selected Example):

.0001 BIRK-AHARONI SYNDROME (1 family)

PSMC1, ILE328THR
ClinVar: RCV002291329

In 3 brothers, born of consanguineous Bedouin parents, with Birk-Aharoni syndrome (BKAH; 620071), Aharoni et al. (2022) identified a homozygous c.983T-C transition (c.983T-C, NM_002802.3) in the PSMC1 gene, resulting in an ile328-to-thr (I328T) substitution at a highly conserved residue in the putative ATP binding site. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including gnomAD. The variant was also absent from 84 unaffected individuals from the same tribe. Expression of the mutation in Drosophila failed to fully rescue the ocular ommatidia defects in Rpt2 (Psmc1)-null flies, whereas wildtype was able to, demonstrating that the mutation causes a functional defect. Aharoni et al. (2022) stated that this mutation is notated as c.764T-C (I225T) based on NM_001330212.2.

REFERENCES

  1. Aharoni, S., Proskorovski-Ohayon, R., Krishnan, R. K., Yogev, Y., Wormser, O., Hadar, N., Bakhrat, A., Alshafee, I., Gombosh, M., Agam, N., Gradstein, L., Shorer, Z., Zarivach, R., Eskin-Schwartz, M., Abdu, U., Birk, O. S.PSMC1 variant causes a novel neurological syndrome. Clin. Genet. 102: 324-332, 2022. [PubMed: 35861243] [Full Text: https://doi.org/10.1111/cge.14195\]
  2. Dubiel, W., Ferrell, K., Pratt, G., Rechsteiner, M.Subunit 4 of the 26 S protease is a member of a novel eukaryotic ATPase family. J. Biol. Chem. 267: 22699-22702, 1992. [PubMed: 1429620]
  3. Gross, M. B.Personal Communication. Baltimore, Md. 2/17/2011.
  4. Hoyle, J., Fisher, E. M. C.Genomic organization and mapping of the mouse P26s4 ATPase gene: a member of the remarkably conserved AAA gene family. Genomics 31: 115-118, 1996. [PubMed: 8808288] [Full Text: https://doi.org/10.1006/geno.1996.0017\]
  5. Matilla, A., Gorbea, C., Einum, D. D., Townsend, J., Michalik, A., van Broeckhoven, C., Jensen, C. C., Murphy, K. J., Ptacek, L. J., Fu, Y.-H.Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex. Hum. Molec. Genet. 10: 2821-2831, 2001. [PubMed: 11734547] [Full Text: https://doi.org/10.1093/hmg/10.24.2821\]
  6. Tanahashi, N., Suzuki, M., Fujiwara, T., Takahashi, E., Shimbara, N., Chung, C. H., Tanaka, K.Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases. Biochem. Biophys. Res. Commun. 243: 229-232, 1998. [PubMed: 9473509] [Full Text: https://doi.org/10.1006/bbrc.1997.7892\]