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Autosomal dominant variants in PSMC5 (HGNC:9552) have been identified in individuals presenting with global developmental delay and intellectual disability consistent with a neurodevelopmental disorder (MONDO:0700092). Heterozygous PSMC5 variants impair proteasome function, leading to neuronal apoptosis and clinical neurodevelopmental phenotypes.
Genetic evidence includes 6 unrelated probands with a recurrent de novo c.959C>G (p.Pro320Arg) variant (PMID:40650163) and three additional individuals carrying heterozygous R325W, Q160A, or a nonsense Q69Ter variant (PMID:38776958), totaling 9 independent cases with consistent heterozygous variants.
Variant spectrum features one recurrent missense, c.959C>G (p.Pro320Arg), and three unique heterozygous alleles: NM_002805.6:c.973C>T (p.Arg325Trp), c.480C>G (p.Gln160Ala), and c.206C>T (p.Gln69Ter). No familial segregation beyond de novo occurrences has been reported, with zero affected relatives identified.
Functional studies demonstrate that PSMC5 insufficiency and the P320R variant weaken the interaction between the 19S regulatory particle and the 20S core particle, reduce proteasome activity, and trigger apoptosis in cellular models, supporting a dominant-negative or haploinsufficiency mechanism (PMID:38776958).
No conflicting evidence for PSMC5’s role in neurodevelopmental disorders has been reported. The convergence of multiple de novo variants and concordant cellular dysfunction supports a causal relationship.
Key take-home: Heterozygous PSMC5 variants cause an autosomal dominant neurodevelopmental disorder via impaired proteasome assembly and neuronal apoptosis, enabling targeted genetic diagnosis and counseling.
Gene–Disease AssociationModerateNine unrelated probands with heterozygous PSMC5 variants and concordant functional data Genetic EvidenceStrongSix de novo c.959C>G (p.Pro320Arg) and three additional heterozygous variants in independent probands Functional EvidenceModerateCellular assays show impaired proteasome assembly and apoptosis consistent with disease mechanism |