2. Academic Validation
  3. PSMC5 insufficiency and P320R mutation impair proteasome function

PSMC5 insufficiency and P320R mutation impair proteasome function

  • Hum Mol Genet. 2024 May 22:ddae085. doi: 10.1093/hmg/ddae085.
Zhong-Qiu Yu 1 2,  Jenny Carmichael 3,  Galen A Collins 4 5,  Maria Daniela D'Agostino 6 7,  Mathieu Lessard 6 7,  Helen V Firth 3,  Pooja Harijan 8,  Andrew E Fry 9 10,  John Dean 11,  Jiuchun Zhang 4,  Usha Kini 12,  Alfred L Goldberg 4,  David C Rubinsztein 1 2
Affiliations

Affiliations

  • 1 Cambridge Institute for Medical Research, The Keith Peters Building, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, United Kingdom.
  • 2 UK Dementia Research Institute, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, United Kingdom.
  • 3 Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Box 134, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
  • 4 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, United States.
  • 5 Department of Biochemistry, Molecular Biology, Entomology, and Plant Pathology, Mississippi State University, 32 Creelman Street, Starkville MS 39762, United States.
  • 6 Division of Medical Genetics, Department of Specialised Medicine, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3J1, Canada.
  • 7 Care for Rare Canada Consortium, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, K1H 8L1, ON, Canada.
  • 8 Department of Paediatric Neurosciences, Box 107, Child development centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom.
  • 9 All Wales Medical Genomics Service, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, United Kingdom.
  • 10 Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom.
  • 11 The School of Medicine, Medical Sciences and Nutrition, Polwarth Building, University of Aberdeen, Aberdeen, AB25 2ZD, United Kingdom.
  • 12 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford & Radcliffe Department of Medicine, University of Oxford, Windmill Road, Oxford, OX3 7HE, United Kingdom.
PMID: 38776958 DOI: 10.1093/hmg/ddae085
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.

Keywords

PSMC5; developmental delay; neurodevelopmental disorder; proteasome; protein degradation.

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