Journal article
PSMC5 insufficiency and P320R mutation impair proteasome function
- Abstract:
- The ubiquitin-proteasome system mediates the degradation of a wide variety of proteins. Proteasome dysfunction is associated with neurodegenerative diseases and neurodevelopmental disorders in humans. Here we identified mutations in PSMC5, an AAA ATPase subunit of the proteasome 19S regulatory particle, in individuals with neurodevelopmental disorders, which were initially considered as variants of unknown significance. We have now found heterozygotes with the following mutations: P320R (6 individuals), R325W, Q160A, and one nonsense mutation at Q69. We focused on understanding the functional consequence of PSMC5 insufficiency and the P320R mutation in cells and found that both impair proteasome function and activate apoptosis. Interestingly, the P320R mutation impairs proteasome function by weakening the association between the 19S regulatory particle and the 20S core particle. Our study supports that proteasome dysfunction is the pathogenic cause of neurodevelopmental disorders in individuals carrying PSMC5 variants
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.9MB, Terms of use)
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- Publisher copy:
- 10.1093/hmg/ddae085
Authors
- Publisher:
- Oxford University Press
- Journal:
- Human Molecular Genetics More from this journal
- Volume:
- 33
- Issue:
- 17
- Pages:
- 1506-1523
- Article number:
- ddae085
- Publication date:
- 2024-05-22
- Acceptance date:
- 2024-05-08
- DOI:
- EISSN:
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1460-2083
- ISSN:
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0964-6906
- Language:
-
English
- Keywords:
- Pubs id:
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2001873
- Local pid:
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pubs:2001873
- Source identifiers:
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W4398193136
- Deposit date:
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2026-08-05
- ARK identifier:
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Terms of use
- Copyright date:
- 2024
- Licence:
- CC Attribution (CC BY)
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