PSMC1 variant causes a novel neurological syndrome

Abstract

Proteasome 26S, the eukaryotic proteasome, serves as the machinery for cellular protein degradation. It is composed of the 20S core particle and one or two 19S regulatory particles, composed of a base and a lid. To date, several human diseases have been associated with mutations within the 26S proteasome subunits; only one of them affects a base subunit. We now delineate an autosomal recessive syndrome of failure to thrive, severe developmental delay and intellectual disability, spastic tetraplegia with central hypotonia, chorea, hearing loss, micropenis and undescended testes, as well as mild elevation of liver enzymes. None of the affected individuals achieved verbal communication or ambulation. Ventriculomegaly was evident on MRI. Homozygosity mapping combined with exome sequencing revealed a disease‐associated p.I328T PSMC1 variant. Protein modeling demonstrated that the PSMC1 variant is located at the highly conserved putative ATP binding and hydrolysis domain, and is suggested to interrupt a hydrophobic core within the protein. Fruit flies in which we silenced the Drosophila ortholog Rpt2 specifically in the eye exhibited an apparent phenotype that was highly rescued by the human wild‐type PSMC1, yet only partly by the mutant PSMC1, proving the functional effect of the p.I328T disease‐causing variant.

Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice

“…In humans, variance of Psmc1 gene is associated with an autosomal recessive syndrome of severe developmental delay and intellectual disability, hearing loss, and other problems [56]. Impaired learning and memory observed from Psmc1 KO mice are consistent with this clinical data, indicating that impaired proteasome could be a driver for the development of an AD-like phenotype.…”

“…In humans, variance of Psmc1 gene is associated with an autosomal recessive syndrome of severe developmental delay and intellectual disability, hearing loss, and other problems [56].…”

Qualitative lysine crotonylation and 2-hydroxyisobutyrylation analysis in the ovarian tissue proteome of piglets

“…Protein degradation through the proteasome pathway is tightly regulated by a variety of proteins to prevent random protein degradation. At the core of the proteasome is the 26S proteasome, a multisubunit proteolytic complex consisting of a central catalytic 20S core particle and a 19S regulatory particle ( Aharoni et al, 2022 ). This regulatory particle binds covalently to a polyubiquitin chain on a protein substrate specifically designed for degradation, thereby specifically controlling the proteolytic function of the proteasome.…”