Developmental and Epileptic Encephalopathies (DEEs) are rare and severe neurological conditions often associated with intellectual disability, developmental delay, autism spectrum disorders and movement disorders. Seizures often begin in early infancy, and patients are often resistant to antiepileptic treatment. Genetic factors play a major role in the underlying cause of many DEEs, and the identification of the causative genes have disclosed unique information on the different pathomechanisms and opened novel therapeutic perspectives.
Recently there has been a plethora of pathogenic variants identified in the γ-aminobutyric acid type A receptor (GABAAR) that causes DEE. This receptor is important as it helps to maintain normal brain activity and variants in GABAAR genes will cause changes to normal brain function. Whole exome sequencing of patients with DEE revealed a large and growing number of disease-causing mutations in 11 out of the 19 genes that code for GABAARs. Mutations are clustered around central functional domains such as the extracellular GABA binding site, transmembrane helices supporting or lining the channel pore or loop regions that couple ligand binding to channel gating. Variants often result in loss of receptor function. However, preliminary data from my laboratory identified variants that lead to a gain of receptor function, an unexpected finding, as patients present with symptoms resembling patients with the opposite functional effect (Absalom et al, unpublished data). Several projects are available. In these projects we aim to gain a better understanding of how variants that cause loss or gain of function receptors lead to DEE and develop a rationale for better treatment options.
1. To determine the pathogenicity of GABAAR variants and categorise these into loss and gain of function mutations that determine whether GABAergic drugs could be used or not;
2. To establish a rank order of treatment options for GABAA receptor mutations against single-mutated subunit receptors that could alleviate epilepsy and developmental deficits; and
3. To understand how loss and gain of function mutations lead to seizures, movement, developmental, and behavioural deficits and, to assess the utility of drugs in knock-in mice.
Our findings will help change the current paradigm of treating patients with DEE using a trial-and-error approach to one that utilises precision medicine based on a patient's genetic, functional and clinical diagnoses.
The project in a multidiscipline collaboration with clinicians at Westmead hospital, and national and international clinical geneticists. Projects may involve combinations of the following: assessing drugs on epilepsy-causing mutations using two-electrode voltage clamp electrophysiology, assessing drugs in epileptic and behavioural rodent models using knock-in mice containing disease-causing mutations, perform immunohistochemistry, autoradiography, binding studies, in situ hybridization and imaging. ________________________________________________________________________________
The research topic falls in the area of neuropharmacology, pharmacology, molecular biology and biochemistry. Candidates should have a strong academic background in one of these areas, and have good verbal and written communication skills. Hands on experience in the techniques is desirable but not essential.
Projects within my laboratory are currently funded by NH&MRC and other external sources.
Please see Professor Collins's Faculty of Medicine and Health Academic Profile for a full list of publications Please see A/Professor Ahring's Faculty of Medicine and Health Academic Profile for a full list of publications Please see Dr. Absalom's Faculty of Medicine and Health Academic Profile for a full list of publications
The opportunity ID for this research opportunity is 2687