A Variant of OTUD3 in Early-Onset Parkinsonism

Early-onset Parkinsonism is a neurodegenerative disorder that can arise from rare genetic variants. We report a 21-year-old female proband with progressive bradykinesia, symmetrical rigidity, resting tremors, postural instability, executive dysfunction, and behavioural disturbances. Brain MRI revealed asymmetric thinning of the substantia nigra pars compacta, consistent with dopaminergic neuronal loss in early-onset Parkinsonism. Exome sequencing identified a novel homozygous missense variant in OTUD3 (c.559C>T; p.Arg187Trp), ultra-rarely present as a heterozygous allele in gnomAD and absent in ClinVar, and inherited in an autosomal recessive manner. The substituted arginine at position 187 lies within a β-sheet of the highly conserved OTU deubiquitinase domain. In silico predictions classified the variant as deleterious, disease-causing, and structurally destabilising. Molecular dynamics simulations additionally predicted R187W-induced destabilisation, including increased backbone flexibility, loss of hydrogen bonding, solvent exposure of the hydrophobic tryptophan residue, and partial collapse of the catalytic domain. In proband-derived fibroblasts, OTUD3-R187W exhibited cytosolic aggregation and failed to regulate its substrate IRP2, resulting in IRP2 accumulation and intracellular iron overload. These cells also showed increased cell death. OTUD3 protein interaction networks and gene ontology analyses revealed involvement in ubiquitin signalling, cytoskeletal organisation, and transcriptional regulation. Together, these data demonstrate that the OTUD3-R187W variant compromises structural integrity and cellular function, contributing to early-onset Parkinsonism. This study implicates OTUD3 as a novel gene linked to neurodegeneration and highlights its role in maintaining midbrain neuronal integrity.