Strengthening the Role of PSMC5 as a Potential Gene Associated with Neurodevelopmental Disorders
Mirella Vinci1, Antonino Musumeci1, Carla Papa1
1Oasi Research Institute-IRCCS, 94018 Troina, Italy.
Insights
A new de novo variant in the PSMC5 gene was identified in individuals with developmental delay and intellectual disability. This finding expands the known neurodevelopmental phenotypes linked to PSMC5 and suggests it as a potential therapeutic target.
Area of Science:
- Molecular Biology
- Genetics
- Neuroscience
Background:
- The 26S proteasome regulates protein homeostasis by degrading ubiquitinated proteins.
- PSMC5, a component of the 26S proteasome, has not been previously linked to a specific phenotype.
- Developmental delay and intellectual disability can stem from disruptions in cellular protein degradation pathways.
Purpose of the Study:
- To investigate the genetic basis of developmental delay and intellectual disability in a patient and his parents.
- To identify and characterize novel genetic variants associated with neurodevelopmental disorders.
- To explore the role of the PSMC5 gene in neurodevelopment.
Main Methods:
- Whole-exome sequencing (WES) was performed on an affected individual and his unaffected parents.
- Bioinformatic analyses, including in silico predictions and protein structure modeling (AlphaFold3), were used to assess the variant's pathogenicity.
- Variant data was cross-referenced with public databases (ClinVar, gnomAD, dbSNP) and literature.
Main Results:
- A de novo variant, c.959C>G (p.Pro320Arg), was identified in the PSMC5 gene.
- The PSMC5 p.Pro320Arg variant was classified as pathogenic by in silico tools and shows strong evolutionary conservation.
- This variant, previously of uncertain significance, was found in six unrelated individuals with similar clinical features and was reclassified as pathogenic in ClinVar.
- AlphaFold3 predicted significant structural alterations in the PSMC5 protein due to the p.Pro320Arg substitution.
Conclusions:
- The PSMC5 p.Pro320Arg variant is associated with developmental delay and mild intellectual disability.
- This study expands the phenotypic spectrum linked to PSMC5 and suggests its critical role in neurodevelopment.
- The identified variant's impact on PSMC5 structure and function may impair 26S proteasome activity, highlighting PSMC5 as a potential therapeutic target.
Abstract:
The 26S proteasome is a large, ATP-dependent proteolytic complex responsible for degrading ubiquitinated proteins in eukaryotic cells. It plays a crucial role in maintaining cellular protein homeostasis by selectively eliminating misfolded, damaged, or regulatory proteins marked for degradation. In this study, whole-exome sequencing (WES) was performed on an individual presenting with developmental delay and mild intellectual disability, as well as on both of his unaffected parents. This analysis identified a de novo variant, c.959C>G (p.Pro320Arg), in the PSMC5 gene. As predicted, this gene shows a very likely autosomal dominant inheritance pattern. Notably, PSMC5 has not previously been associated with any phenotype in the OMIM database. This variant was recently submitted to the ClinVar database as a variant of uncertain significance (VUS) and remains absent in both gnomAD and dbSNP. Notably, it has been identified in six unrelated individuals presenting with clinical features comparable to those observed in the patient described in this study. Multiple in silico prediction tools classified the variant as pathogenic, and a PhyloP conservation score supports strong evolutionary conservation of the mutated nucleotide. Protein structure predictions using the AlphaFold3 algorithm revealed notable structural differences between the mutant and wild-type PSMC5 proteins. We hypothesize that the p.Pro320Arg substitution alters the structure and function of PSMC5 as a regulatory subunit of the 26S proteasome, potentially impairing the stability and activity of the entire complex. Although functional studies are imperative, this study contributes to a deeper understanding of PSMC5, expands the spectrum of associated neurodevelopmental phenotypes, and highlights its potential as a therapeutic target. Furthermore, this study resulted in the submission of the identified variant to the ClinVar database (SCV006083352), where it was classified as pathogenic.
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