Developmental and epileptic encephalopathy (DEE) refers to a group of neurodevelopmental conditions characterized by developmental delay, cognitive impairment, and seizures in children. In 2016, the first case linking variants in both the copies of UBA5 gene to DEE44 was reported. Since then, twelve distinct missense variants in the UBA5 gene have been identified in 25 patients.
to humans. It encodes a protein that binds to Ubiquitin-fold Modifier 1 and was discovered two decades ago. It acts as an enzyme that catalyzes a post-translational modification called UFMylation. The exact mechanisms and biological significance of UFMylation are still unclear, but it adds a new regulatory layer to many fundamental cellular processes.
They found that the severity and the type of symptoms varied widely among different variants. For instance, they found four variants that failed to rescue the lethality caused by the loss of endogenous Uba5. Another five variants caused progressive motor defects, three of which also caused developmental delays or seizure-like symptoms.
In collaboration with Dr. Jonathan Pruneda and Dr. Ruth Napier at Oregon Health & Science University and the Raiden Science Foundation of Beaverton, Oregon, the team also established several new biochemical assays to determine the impact of these disease alleles on the stability and activity of the UBA5 enzyme.
"We undertook this study because there was a clear need to assess the disease-associated variants of UBA5," Dr. Bellen said."This study not only established a powerful experimental paradigm to better understand the etiology of DEE44 but can also serve as a template to better understand other human disorders and to develop new therapies for DEE44 and others."
Others involved in the study were Albert N. Alvarez, Mengqi Ma, Shenzhao Lu, Michael W. Crawford, Lauren C. Briere, Oguz Kanca, Shinya Yamamoto, David A. Sweetser, Jenny L. Wilson, Ruth J. Napier, and Jonathan N. Pruneda.Xueyang Pan et al, Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays,
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