Genetics of AS 101: Why Better Therapeutics are Possible

Quick Overview

Rebecca Burdine, a molecular biology professor at Princeton University, discusses the genetics of Angelman syndrome (AS) and the potential for better therapeutics. She explains the difference between genotypes and phenotypes, emphasising that AS is caused by the lack of the UBE3A gene’s function in the brain. This gene is crucial for recycling proteins, and its absence leads to a build-up of non-functional proteins, affecting neuron function. Burdine outlines the genetic mechanisms leading to AS, including deletions, mutations, and imprinting defects, and reassures parents that these are not caused by their actions.

She highlights the importance of understanding the genetic basis of AS for developing therapies, such as using viruses to deliver UBE3A or antisense oligonucleotides to reactivate the paternal copy of the gene. Burdine stresses the need for clinical trials to test these therapies and encourages participation. She also advises on managing AS symptoms, focusing on health, communication, and behaviour, and underscores the importance of supportive communities and self-care for parents. Burdine concludes by advocating for sensitive language when discussing AS, emphasising the potential for individuals with AS to learn and thrive.

Rebecca Burdine, a professor of molecular biology at Princeton University, delivered an insightful talk at the 2024 ASF Family Conference, focusing on the genetics of Angelman syndrome (AS) and the potential for developing better therapeutics. Her presentation was not only informative but also deeply personal, as she shared her experiences as a parent of a child with Angelman syndrome.

Understanding Angelman Syndrome

Angelman syndrome is a genetic disorder that primarily affects the nervous system. Burdine explained the basic genetic concepts of genotypes and phenotypes, emphasising the importance of understanding the genetic makeup (genotype) and how it manifests in individuals (phenotype). She highlighted the unique genetic mechanism in mammals, where the body recognises which DNA strand comes from the mother and which from the father, a process known as genetic imprinting.

The disorder is linked to the UBE3A gene located on chromosome 15. In most cells, both maternal and paternal copies of this gene are active. However, in neurons, the paternal copy is silenced, leaving only the maternal copy to function. This silencing is a key factor in Angelman syndrome, as any disruption to the maternal UBE3A gene can lead to the disorder.

The Role of UBE3A

UBE3A is a protein that acts as a recycling mechanism within cells, identifying and marking proteins that need to be degraded. Without functional UBE3A, proteins accumulate in neurons, disrupting their function. Burdine likened this to a car that isn’t properly tuned, where all parts are present but not working in harmony.

Genetic Mechanisms and Mutations

Burdine detailed the various genetic mechanisms that can lead to Angelman syndrome, including deletions, mutations, uniparental disomy (UPD), and imprinting defects. She reassured parents that these genetic changes often occur long before conception, alleviating concerns about parental actions causing the disorder.

Symptoms and Variability

Angelman syndrome is characterised by consistent symptoms such as nonverbal communication, movement and balance issues, developmental delays, and distinctive EEG patterns. However, the severity and combination of symptoms can vary widely among individuals. Burdine noted that while some children may have severe symptoms, others with similar genetic profiles may function remarkably well, highlighting the complexity of the disorder.

Current and Future Therapeutics

While current treatments focus on managing symptoms, such as seizures and sleep issues, Burdine expressed optimism about future therapeutics. She discussed two main strategies: replacing the missing UBE3A protein using viral vectors and enhancing the expression of the paternal UBE3A gene using antisense oligonucleotides. These approaches aim to restore UBE3A function in the brain, potentially alleviating the symptoms of Angelman syndrome.

The Importance of Community and Support

Burdine emphasised the importance of community support and self-care for families affected by Angelman syndrome. She encouraged parents to prioritise their health and well-being, as it directly impacts their ability to care for their children. She also highlighted the value of supportive communities and the potential pitfalls of social media, which can sometimes exacerbate feelings of isolation and depression.

Conclusion

Rebecca Burdine’s talk provided a comprehensive overview of the genetics of Angelman syndrome and the promising avenues for therapeutic development. Her personal insights and scientific expertise offered hope and encouragement to families navigating the challenges of this complex disorder. As research progresses, the potential for effective treatments continues to grow, bringing new possibilities for improving the lives of those affected by Angelman syndrome.