Pathway-driven discovery of epilepsy genes

Abstract

Epilepsy genes deliver critical insights into the molecular control of brain synchronization and are revolutionizing our understanding and treatment of the disease. The epilepsy-associated genome is rapidly expanding, and two powerful complementary approaches, isolation of de novo exome variants in patients and targeted mutagenesis in model systems, account for the steep increase. In sheer number, the tally of genes linked to seizures will likely match that of cancer and exceed it in biological diversity. The proteins act within most intracellular compartments and span the molecular determinants of firing and wiring in the developing brain. Every facet of neurotransmission, from dendritic spine to exocytotic machinery, is in play, and defects of synaptic inhibition are over-represented. The contributions of somatic mutations and noncoding microRNAs are also being explored. The functional spectrum of established epilepsy genes and the arrival of rapid, precise technologies for genome editing now provide a robust scaffold to prioritize hypothesis-driven discovery and further populate this genetic proto-map. Although each gene identified offers translational potential to stratify patient care, the complexity of individual variation and covert actions of genetic modifiers may confound single-gene solutions for the clinical disorder. In vivo genetic deconstruction of epileptic networks, ex vivo validation of variant profiles in patient-derived induced pluripotent stem cells, in silico variant modeling and modifier gene discovery, now in their earliest stages, will help clarify individual patterns. Because seizures stand at the crossroads of all neuronal synchronization disorders in the developing and aging brain, the neurobiological analysis of epilepsy-associated genes provides an extraordinary gateway to new insights into higher cortical function.

Building a zebrafish toolkit for investigating the pathobiology of epilepsy and identifying new treatments for epileptic seizures

“…Indeed, genetic analysis of specific forms of inherited epilepsy, along with GenomeWide Association Studies (GWAS) and exome sequencing studies of large cohorts of epilepsy patients and controls, have identified epilepsy-associated sequence variants in hundreds of genes with a wide variety of roles in nervous system development and function (Noebels, 2015). Many of these genes encode neuronal proteins that regulate membrane excitability, such as ion channels, neurotransmitter receptors and transporters (Deng et al, 2014), or factors controlling synaptic vesicle formation, release and trafficking (Casillas-Espinosa et al, 2012).…”

The Future of Next-Generation Sequencing in Neurology

“…As such, the mechanisms of disease will continue to be elucidated. This progression in unraveling complex genetic diseases is illustrated by the pathway-driven discovery of epilepsy genes 5 and by the discernment of gene networks associated with autism. 6 …”

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

“…98,99 In mice and humans, a combination of empirical evidence and literature review has begun to define the circuitry of networks associated with disease. 100,101 In many species, modifier genes are readily identified for both simple and complex traits. With these emerging resources and technologies, specifying network components, their dependencies, and targets for interventions is increasingly feasible, especially for specific conditions and diseases.…”