
Understanding UBE3A Variants: A New Tool for Angelman Syndrome Research
Around 10% of Angelman syndrome cases are caused by specific changes in the UBE3A gene, but many of these genetic variants are classified as “uncertain” or “conflicting,” making it difficult for doctors to determine their impact. Adding to the complexity, some mutations increase UBE3A activity, leading to different symptoms than the typical loss of function seen in Angelman syndrome.
Our lab has developed a new biosensor to accurately measure UBE3A activity, even at normal levels found in the body. This tool can distinguish harmful mutations that reduce or increase UBE3A activity from those that have no effect. Early tests have shown its ability to classify known mutations with high accuracy.
Why It Matters
This biosensor could revolutionize diagnosis and research by:
- Helping classify uncertain UBE3A variants.
- Measuring UBE3A activity in patient-derived cells.
- Providing clearer answers for families and supporting better treatments for Angelman syndrome.
By bridging the gap between genetic testing and clinical care, this tool offers new hope for understanding and managing UBE3A-related conditions.
One of my long-term goals is to develop a disease-modifying treatment for Angelman syndrome. Treatments like ASOs and genome editors that unsilence the paternal UBE3A allele show incredible promise. With support from the ASF, our lab was the first to show that Cas9-based genome editors can be used to unsilence the dormant paternal UBE3A allele in mouse and human neurons. One of the major remaining challenges has been determining if individuals with small mutations that alter UBE3A protein are likely to develop Angelman syndrome. The biosensor that we will develop as part of this project has the sensitivity to determine if UBE3A is abnormally low or high in cells, including brain and blood cells. This biosensor could be used to identify those individuals who might benefit from ASOs and genome editors that are in development for the treatment of Angelman syndrome.
– Mark Zylka, PhD