Publication Date
7-11-2024
Journal
American Journal of Human Genetics
DOI
10.1016/j.ajhg.2024.05.016
PMID
38866022
PMCID
PMC11267520
PubMedCentral® Posted Date
6-11-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Adolescent, Animals, Child, Child, Preschool, Female, Humans, Male, Drosophila melanogaster, Intellectual Disability, Interferons, Loss of Function Mutation, Neurodevelopmental Disorders, Obesity, Phenotype, Proteasome Endopeptidase Complex
Abstract
Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be recapitulated in Drosophila melanogaster with depletion of the PMSD11 ortholog Rpn6, which compromised reversal learning. Our investigations in subject samples further revealed that PSMD11 loss of function resulted in impaired 26S proteasome assembly and the acquisition of a persistent type I interferon (IFN) gene signature, mediated by the integrated stress response (ISR) protein kinase R (PKR). In summary, these data identify PSMD11 as an additional member of the growing family of genes associated with neurodevelopmental proteasomopathies and provide insights into proteasomal biology in human health.
Graphical Abstract
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