Florey Department of Neuroscience and Mental Health - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemInvestigating SCN2A dysfunction in later-onset epileptic encephalopathy and autism( 2022)Voltage-gated sodium channels are protein complexes that underlie action potential electrogenesis in excitable cells. Genetic variation in channel genes is a major cause of neurodevelopmental disorders including epilepsy, autism spectrum disorder (ASD), and intellectual disability. SCN2A, encoding voltage-gated sodium channel 1.2 (NaV1.2), is one of the most significant single-gene contributors in all neurodevelopmental disorders, with genetic variants reported in several conditions ranging in severity from benign temporary seizure syndromes to phenotypically devastating developmental and epileptic encephalopathies. Genetic variants in SCN2A are typically described as either gain- or loss-of-function (LOF), with evidence to suggest that there is strong correlation between genotype and phenotype. SCN2A ASD and later-onset developmental and epileptic encephalopathy (LOEE) are severe life-long disorders with no targeted pharmacological interventions currently available. Anti-epileptic pharmaceuticals have variable efficacy in treating the seizures associated with LOEE, and they do not target the associated features of the disorder, some of which are common with ASD, including intellectual disability, developmental delay, movement disorders, and behavioural issues. This thesis is the culmination of four years of study of voltage-gated sodium channel patients, gene regulation, and neuron models, and includes the first phenotypic analysis of patient-derived induced-pluripotent stem cell (iPSC) models of SCN2A in ASD and LOEE, two developmental disorders with enigmatic mouse models and an unmet clinical need. This project is designed to elucidate the mechanisms behind LOF SCN2A in these two disorders using electrophysiological and molecular techniques on selected candidate variants in each disorder. The hypothesis of this PhD project is that patient-derived iPSC models of SCN2A LOF will reveal disorder-specific phenotypes in neurons, informing the pathomechanisms of disease and useful for future drug screening projects. This thesis is divided into four chapters, each chapter exploring a different aspect of SCN2A in development and disease. Chapter 1 serves as an introduction to sodium channel subtypes, structure, function, and contains a review of the SCN2A literature describing patient genetic variants, associated phenotypes, published laboratory models and therapeutic strategies. Chapter 2 is a published study on the developmental expression and transcript regulation of voltage-gated sodium channel genes relevant to neurodevelopmental disorders. Chapters 3 and 4 explore the pathomechanisms of disease in SCN2A LOEE and ASD, respectively, and include the first functional characterisation of SCN2A patient-derived iPSC models of these disorders.