PSMC3 – Neurodevelopmental Disorder

PSMC3 encodes the AAA-ATPase subunit Rpt5 of the 26S proteasome, essential for protein substrate unfolding and degradation. Heterozygous de novo missense variants in PSMC3 have been identified in patients presenting with global developmental delay and intellectual disability, establishing an autosomal dominant inheritance for a neurodevelopmental disorder. Initial candidate gene evidence emerged from CNV analysis in a Bangladeshi NDD cohort, where PSMC3 was among 18 critical-exon genes in focal pathogenic CNVs ([PMID:36959829]).

In a cohort of 23 unrelated patients, 15 distinct de novo missense variants in PSMC3 were identified, each associated with neurodevelopmental delay ([PMID:37256937]). The variants cluster within domains crucial for substrate translocation, with one recurrent change c.777G>A (p.Met259Ile) detected in multiple probands. All reported cases exhibited global developmental delay (HP:0001263) and intellectual disability (HP:0001249). Segregation analysis is limited by de novo occurrence, with no additional affected relatives.

Functional studies support a pathogenic mechanism of proteasome dysfunction. Expression of patient-derived PSMC3 variants in mouse neuronal cultures impairs dendrite development, while knockdown of the Drosophila ortholog Rpt5 disrupts learning and memory phenotypes ([PMID:37256937]). Proteomic and transcriptomic profiling of patient T cells revealed accumulation of ubiquitinated substrates, activation of proteotoxic stress pathways, and dysregulated type I interferon signaling.

Rescue experiments demonstrate that inhibition of the intracellular stress sensor PKR normalizes interferon responses, highlighting a mechanistic link between variant-induced proteasome impairment and neurodevelopmental pathology. Concordance across cellular, animal, and patient-derived models underscores the gene’s role in neural development.

No conflicting reports have been identified. Cumulative evidence meets criteria for a strong gene–disease association, with robust genetic and functional concordance.

Key Take-home: PSMC3 de novo missense variants cause an autosomal dominant neurodevelopmental disorder through proteasome dysfunction and proteotoxic stress, supporting genetic testing and potential targeting of stress pathways in affected individuals.

References

• Frontiers in genetics • 2023 • Construction of copy number variation landscape and characterization of associated genes in a Bangladeshi cohort of neurodevelopmental disorders. PMID:36959829
• Science translational medicine • 2023 • PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production. PMID:37256937

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