Researchers from The Florey, the University of Sydney and the University of Southern Denmark, supported by Phenomics Australia, have shown that certain GABRA3 variants do cause epilepsy and developmental problems. Importantly, they discovered that the severity of disease among people with these gene mutations can vary dramatically.
Key points
- Epilepsy is one of the most common neurological conditions, affecting one in 25 people.
- The severity of epilepsy varies among those living with the condition and can be influenced by genetics, brain function and environmental and personal factors.
- Experts from The Florey have contributed to international research that has uncovered new genetic insights that could lead to improved diagnosis and treatment of certain types of epilepsy.
- The first mouse model of gain-of-function GABRA3-associated epilepsy was produced via CRISPR genome editing by the Monash Genome Modification Platform, Monash University, a node of Phenomics Australia.
This story was first published on The Florey’s website.
Between 30-40 percent of people living with epilepsy have a family history of the disease, but the pattern of inheritance differs depending on the type of genetic mutation involved.
Previous research has found a link between epilepsy and GABRA3 receptor gene mutations (inherited through the X-chromosome), but the effect of the mutations on carriers has been unclear.
Now, researchers from The Florey, the University of Sydney and the University of Southern Denmark, supported by Phenomics Australia, have shown that certain GABRA3 variants do cause epilepsy and developmental problems. Importantly, they discovered that the severity of disease among people with these gene mutations can vary dramatically.
The research, published in The Journal of Clinical Investigation, demonstrated that it is the functional impact of the gene variant, not its mere presence, that determines its effect on an individual.
To better understand the role of GABRA3 gene mutations, researchers studied 43 people with 19 different GABRA3 variants and found two distinct categories: those that worked too well (gain-of-function variants) and those that worked poorly (loss-of-function variants).
Gain-of-function variants were associated with severe, treatment-resistant epilepsy and profound intellectual disability, disproportionately affecting males.
Loss-of-function variants produced milder disease traits, with epilepsy rarely seen. Affected males displayed behavioural issues and language delay, while females were unaffected carriers.
Head of The Florey’s Epilepsy and Neurodevelopment Research Priority and co-author, Professor Christopher Reid, said the results were surprising because they dispelled a long-held assumption.
“The thinking was that all disease-causing GABRA3 variants were loss-of-function mutations. We now know that some variants instead increase receptor activity and are linked to much more severe epilepsy,” Professor Reid said.
“Working with A/Prof Ahring from The University of Sydney highlight how important collaborations are for answering complex questions relating to pathological mechanisms in rare disease”
Co-author Associate Professor Philip K. Ahring said that developing and breeding these mice was extremely challenging, and that the new findings were only possible because of close collaboration between researchers in Australia and internationally, along with strong support from the Monash Genome Modification Platform.
“Our results help explain long-standing questions about GABRA3. Importantly, they also show that the effect of a genetic variant, whether it increases or reduces receptor function, shapes disease severity and the outcome of inheritance, bringing a new dimension to our understanding of X-linked disorders”, A/Prof Ahring said.
Research Fellow, Dr Khaing Phyu Aung, led The Florey’s contribution to the research by using the first mouse model of gain-of-function GABRA3-associated epilepsy to support the team’s findings.
The Gabra3 p.(Gln242Leu) knock-in mouse model was produced via CRISPR genome editing by the Monash Genome Modification Platform, Monash University, a node of Phenomics Australia.
“These models are powerful tools for uncovering disease mechanisms and can also be used to test potential new therapies, bringing hope for improved treatments for individuals affected by this devastating condition,” Dr Aung said.
“Clarifying the role of GABRA3 mutations in epilepsy will allow for more informed genetic counselling, more targeted medicine and will also help more broadly to interpret X-linked neurodevelopmental disorders.”
