New Study Uncovers the Severity of UBA5 Gene Variants Linked to Developmental and Epileptic Encephalopathy (DEE44)
In a groundbreaking study conducted by Dr. Hugo J. Bellen and his team at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and Baylor College of Medicine, new insights have been revealed regarding the severity of UBA5 gene variants associated with Developmental and Epileptic Encephalopathy (DEE44). DEE is a neurodevelopmental condition characterized by developmental delay, cognitive impairment, and seizures in children.
The first case identifying the connection between UBA5 gene variants and DEE44 was reported in 2016. Since then, researchers have identified twelve distinct missense variants in the UBA5 gene, affecting a total of 25 patients. To further enhance our understanding of this rare disorder, Dr. Bellen’s team developed a fruit fly model to assess the impact of each variant on symptom severity.
The UBA5 gene is highly conserved across various species, including humans and fruit flies. It encodes a protein that binds to Ubiquitin-fold Modifier 1 (UFM1) and plays a crucial role as an enzyme in a post-translational modification known as UFMylation. UFMylation’s exact mechanisms and biological significance are yet to be fully understood, but it adds a new regulatory layer to several fundamental cellular processes.
By expressing the human version of the UBA5 gene in fruit flies lacking the endogenous Uba5 gene, Dr. Pan and his team were able to create a humanized model for their study. This unique approach allowed them to evaluate the disease-causing variants individually and observe the resulting phenotypes.
The study findings displayed remarkable diversity in symptom severity and type among the different UBA5 variants. Four variants failed to rescue the lethal effects caused by the loss of endogenous Uba5, while another five variants caused progressive motor defects. Three of these five variants also induced developmental delays or seizure-like symptoms. Interestingly, the normal human UBA5 gene functioned in place of its fly counterpart seamlessly. However, the disease-causing variants exhibited varying degrees of loss of function classified as mild, intermediate, or severe subtypes. Encouragingly, exogenous overexpression of the UBA5 gene did not produce any discernible defects, suggesting a potentially safe therapeutic strategy to increase UBA5 enzyme levels.
In collaboration with Dr. Jonathan Pruneda and Dr. Ruth Napier at Oregon Health & Science University and the Raiden Science Foundation, the team developed new biochemical assays to determine how these disease alleles impact the UBA5 enzyme’s stability and activity. The results revealed a strong correlation between the severity of symptoms observed in fruit flies and the enzymatic stability and/or function of a specific UBA5 variant. This molecular understanding of the loss of function in UBA5 variants paves the way for the development of novel drugs targeting UBA5 restoration for the treatment of DEE44 and other related disorders.
Dr. Bellen emphasized the significance of this study, not only in deepening our understanding of DEE44 but also in potentially stimulating the development of therapies for this condition and others. The research model established by Dr. Bellen’s team has the potential to further our comprehension of various human disorders and guide the exploration of new treatment options.
This study represents a significant step forward in the pursuit of effective treatments for DEE44. By shedding light on the severity and impact of specific UBA5 gene variants, researchers have laid a solid foundation for future evaluations, drug development, and potential gene therapies. The hope is that these advancements will ultimately improve the lives of individuals living with this rare disorder, offering them renewed hope for a better future.
The research team involved in this study included 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.
