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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\u2010associated p.I328T <jats:italic>PSMC1<\/jats:italic> 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\u2010type PSMC1, yet only partly by the mutant PSMC1, proving the functional effect of the p.I328T disease\u2010causing variant.<\/jats:p>","DOI":"10.1111\/cge.14195","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T10:44:27Z","timestamp":1658400267000},"page":"324-332","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["<scp><i>PSMC1<\/i><\/scp> variant causes a novel neurological syndrome"],"prefix":"10.1111","volume":"102","author":[{"given":"Sarit","family":"Aharoni","sequence":"first","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences Ben\u2010Gurion University of the Negev  Beer Sheva 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