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PSMC5 insufficiency and P320R mutation impair proteasome function.

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Yu, Zhong-Qiu 
Carmichael, Jenny 
Collins, Galen A 
D'Agostino, Maria Daniela 
Lessard, Mathieu 


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.



PSMC5, developmental delay, neurodevelopmental disorder, proteasome, protein degradation

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Hum Mol Genet

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Oxford University Press (OUP)
UK Dementia Research Institute (Unknown)
PSMC5 Foundation (PSMC5 P312R)
We are very grateful for funding from the PSMC5 Foundation, Board Members: Idit & Joe Silverman and Michelle & Clint Myers and all the generous friends, families, and contributing organizations, and UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), Rosetrees Trust and the NIHR Cambridge Biomedical Research Centre (NIHR203312). The DDD study was supported by a grant (HICF-1009-003) from the Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the Department of Health, and a grant (WT098051) from the Wellcome Sanger Institute. A.L.G. was supported by the NIH-National Institute of General Medical Sciences (R01 GM51923) and Cure Alzheimer’s Fund.