Abstract
E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the presence of autism, epilepsy, and, in some probands, a movement disorder. E3 ubiquitin ligases are responsible for transferring ubiquitin to substrate proteins to regulate a variety of cellular functions, including protein degradation, protein-protein interactions, and protein localization. Knocking out ubr-5 in C. elegans resulted in a lower movement score compared to the wild type, supporting a role for UBR5 in neurodevelopment. Using an in vitro autoubiquitination assay and confocal microscopy for the human protein, we found decreased ubiquitination activity and altered cellular localization in several variants found in our cohort compared to the wild type. In conclusion, we found that variants in UBR5 cause a neurodevelopmental syndrome that can be associated with a movement disorder, reinforcing the role of the UBR protein family in a neurodevelopmental disease that differs from previously described ubiquitin-ligase-related syndromes. We also provide evidence for the pathogenic potential loss of UBR5 function with functional experiments in C. elegans and in vitro ubiquitination assays.