Affects of Faulty UBE3A Mutations Point to Potential Therapeutic Strategies for Angelman
More than 90 percent of Angelman syndrome cases are caused by genetic abnormalities affecting the E3 ubiquitin ligase (UBE3A) gene.
In the study “A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders,” a team at Georgia State University reviewed what is known about this enzyme and its role in the development of this neurological disorder. The study was published in the journal Frontiers in Genetics.
There are about 660 genes encoding E3 ubiquitin ligases. Of these, 19 genes have been linked to common neurological disorders, and 51 are associated with rare disorders, including Angelman syndrome.
While genetic mutations in E3 ubiquitin ligases coding genes have been well-documented, little is known about their contribution for the development of rare neurological disorders.
Mice Models of Disease
To better understand the role of UBE3A mutations in Angelman syndrome, mice models of the disease have been genetically engineered. These animals were found to show similar motor and behavioral responses as those observed in human patients. Analysis of nerve cells confirmed abnormal structures and reduced responsiveness and plasticity, affecting the area of the brain that controls vision.
Further evaluation of brain structures revealed that Angelman syndrome mice have changed anatomical differences across multiple brain regions, compared to healthy animals. They have smaller heads (microcephaly) and have significant reductions in white matter areas, characteristics linked to early neurological damage and seizures.
Given the sticking affect of UBE3A mutations, restoration of normal UBE3A enzyme levels has been tested as potential treatment for this rare neurological disorder.
Restoring UBE3A activity in adolescent Angelman mice models rescued motor deficits by improving nerve cells responsiveness and activity. However, symptoms such as anxiety, repetitive behavior, and epilepsy could be overcome only if the treatment was applied early during development.
We have two copies of every gene in our body; one is inherited from the mother and a second one from the father. However, the UBE3A gene undergoes a process called imprinting, which silences the paternal copy, allowing the readout of the maternal version only.
This means that Angelman patients have a faulty UBE3A maternal version and may carry a healthy copy from the father.
As such, it may be possible to reduce the impact of UBE3A mutations by promoting the production of the healthy proteins derived from the paternal version of the gene.
This strategy has led to improved UBE3A enzyme levels and nerve cell structures in preclinical studies, demonstrating potential to revert some of the characteristic Angelman syndrome features such as intellectual impairment and developmental delay.
Still, further research is necessary to address the full beneficial impact of this type of therapeutic mechanism.
Even when the maternal UBE3A gene version is the correct one, if it exists in a duplicated form it also will cause Angelman syndrome.
Finding a way to ensure the production of the right amount of UBE3A enzyme is a crucial step to find a treatment for this rare disease.
Despite scientific advancements, there are still many unanswered questions to fully understand E3 ubiquitin ligases’ contributions toward neurodevelopmental diseases and their potential as therapeutic targets, according to researchers.
“Due to the emergence of early symptoms in Angelman syndrome and autism spectrum disorders, individuals with UBE3A disruptions can be monitored throughout their lifetime to prevent or alleviate ongoing symptoms such as seizures or ataxia,” the review concluded.