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.

Figure 1

Inherited gene variants are discovered in human epilepsy pedigrees and de novo variants are detected in proband-parental trios. These require physiological verification in orthologous models to demonstrate epileptic phenotypes. Pathway-driven candidate genes are mutagenized and validated in models for rediscovery in human exomes. Each revolution of this discovery cycle results in a validated diagnostic gene and an experimental biological test system to search for therapy. IPSC, induced pluripotent stem cell.

Figure 2

A significant monogenic driver pathway for epilepsy can be constructed from current gene evidence implicating mutations in genes that impair every aspect of synaptic inhibitory transmission from early development through maturation of adult GABA neurotransmission. Only a partial listing of known genes is shown, and many others remain to be functionally assigned to their target location and impact on excitation and inhibition in epileptic microcircuits.

Figure 3

Two extreme examples of single and multigenic biological complexity in epileptic brain. Left, epileptic phenotype in mouse mutant with a solitary Nova2 knockout arises from alterations in splice patterns of a cassette of 34 synaptic proteins (reproduced with permission from ref. 78). Many of these targets are known monogenic causes of epilepsy. Right, extensive multigenic complexity in the ion channel variant profile (channotype) of individuals with sporadic epilepsy is similar to that found in unaffected cases. Many affected individuals show multiple non-synonymous single nucleotide variants in human epilepsy genes (hEP), and clinical status depends on the pattern, not absolute load, of variants. In silico modeling of combinatorial effects of multiple ion channel variants in a single model neuron demonstrates how profiles produce a spectrum of single cell firing patterns (reproduced from ref. with permission from Elsevier).