biostudies-literatureUnknownMagrinelli FWellcome TrustDissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify <i>PSMF1</i> as a novel gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic <i>PSMF1</i> missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 17 pedigrees with 24 affected subjects, showing clear genotype-phenotype correlation. <i>PSMF1</i> encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodemedRxiv : the preprint server for health sciences2024.06.19.24308302https://www.ebi.ac.uk/biostudies/studies/S-EPMC11326324biostudies-literatureVariants in the proteasome regulator PSMF1 cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality and disrupt mitochondrial function.PMC11326324Hershkovitz TAlvi JRHaack TBFroukh TAlessi DRSvetel MBarisic NAlkhawaja IATesson CMaroofian RMonfrini EBuchert RBauer PCassar MHardy JAAngelova PRChui MMCavallieri FDi Fonzo AVolin MHoulden HYuksel GANg EWBrice AChung BHKiziltan GNirujogi RYalcın-Cakmakli GAlrukban HAEMurphy DFauth CGandhi SMakarious MBSeverino MParchi PBhatia KPBertoli-Avella AMHassan BATinazzi MSultan TBreedveld GJLis PElibol BEsteras NKwong AKLesage SScardamaglia AZech MBlauwendraat CZoggeler TFan SSSalazar-Villacorta AAlavi SLewis PARodriguez JAWeiss KStals KPitz VSteinfeld RPinon CMammana ASofan LAbramov AYIftikhar SPSMF1 Study GroupKurtis MMBasak ANLowe SASteller HShimazu JCourtin TJaconelli MEfthymiou SBonifati VO'Callaghan BObeso JACogan GMagrinelli FRocca CSchatz UAHanagası HABaiardi STireli HJepson JECSantangelo MVarghese VBilgic BVona BSamanci BGul-Demirkale TfalseVariants in the proteasome regulator PSMF1 cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality and disrupt mitochondrial function.Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify <i>PSMF1</i> as a novel gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic <i>PSMF1</i> missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 17 pedigrees with 24 affected subjects, showing clear genotype-phenotype correlation. <i>PSMF1</i> encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurode2025-01-01T00:00:00Z2025 Jul2026-06-30T03:20:01.492Z2024-11-08T22:31:12.9ZS-EPMC113263243914884010.1101/2024.06.19.24308302