Relevance to Autism

Yu et al., 2024 described a cohort of seven individuals (two of whom were from DECIPHER) with heterozygous variants in the PSMC5 gene and presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and behavioral anomalies, including five individuals with autism spectrum disorder or autistic features; functional assessment of a recurrent p.Pro320Arg missense variant that was arose de novo in four individuals from this cohort (three of whom presenting with autism spectrum disorder) demonstrated impaired proteasome function by reduced association between the 19S regulatory particle and the 20S core particle. Three additional ASD probands (one from the Simons Simplex Collection, two from the SPARK cohort) were also found to have de novo missense variants in the PSMC5 gene that were predicted to be deleterious (REVEL > 0.5) and were either absent or very rare in both ExAC and gnomAD; one of the SPARK probands carried the functionally relevant p.Pro320Arg missense variant. Kury et al., 2025 identified 44 individuals with 26 distinct PSMC5 variants presenting with a syndromic neurodevelopmental disorder characterized by global developmental delay, delayed or absent speech, intellectual disability, motor delay or impairment, abnormal behavior (including autism spectrum disorder and ADHD), abnormal muscle tone, and seizures, as well as additional non-neurological findings and a similar facial gestalt; additional functional analyses performed on patient cells and animal models in this report demonstrated that PSMC5 alterations led to a loss of proteasome function, leading to protein aggregation, disruption of mitochondrial homeostatis, and dysregulation of lipd metabolism and immune signaling, as well as compromised synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions such as learning and locomotion.

Molecular Function

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. In addition to participation in proteasome functions, this subunit may participate in transcriptional regulation since it has been shown t

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References