Jgp_201711759 533..546

533 Introduction The dual premise that inherited monogenic errors in membrane ion currents cause disease, and that drugs designed to restore the biophysics of defective voltage-gated channels hold the key to correcting them is over 50 years old and remains unshaken. Breakthroughs in visualizing, modeling, and optically controlling pore regions of voltage gated-channels, including alternative voltage-sensing (Whicher and MacKinnon, 2016) and temperature sensitive (Arrigoni et al., 2016) domains, combined with the widening search for therapeutic peptide toxins (Verdes et al., 2016) and synthetic allosteric modulators (Changeux and Christopoulos, 2016), all signal continuing grounds for unbridled optimism, even while leaving significant kinetic properties unexplained (Hoshi and Armstrong, 2015). Now a third wave of discovery is unfolding, driven by the steady drumroll of genetic variants within subunits of this molecular superfamily detected by exome sequencing in cases of human epilepsies and cognitive disorders appearing at the earliest stages of life. The challenge to isolate and repair the pathogenic mechanisms of these experiments of nature provides an overarching scientific framework to explore links between the genetic refinement of ion channel biophysics with their cellular biology and to trace the critical steps toward their highest evolutionary achievement, synchronizing neurons in the human neocortex. Why study channel disorders in epileptic cortical microcircuits in preference to single cell models? Brain tissue is the single largest repository of membrane bound proteins (Uhlén et al., 2015), and enrichment of ion channel gene mutations in epilepsy, a prototypical neuronal synchronization disorder affecting nearly 1% of the world population, comes as little surprise. The first 10 genes linked to epilepsy in humans and mouse genetic models were all subunits of voltageand ligand-gated ion channels, which currently constitute nearly one third of nearly 150 known monogenic causes of seizure disorders (Noebels, 2015a). Subsets of these channel genes overlap with those for other disorders such as ataxia, autism, and cognitive development and memory impairment (Spillane et al., 2016), creating a genetic borderland of single channel comorbidities with many different circuits affected by shared molecular errors (Noebels, 2015b). Because individual neurons express up to 300 different channel subunits and develop unique use-dependent cell and isoform-specific profiles, an inherited variant may be tolerated in one neural pathway and damaging in another. The technical simplicity of a transfected heterologous model cell to determine alterations of activation kinetics, an efficient first step, cannot accurately reflect the dynamic and cell-specific compartmental density of the current and can only suggest rather than explain why, where, or when synchronization in a given network will be impaired. Nevertheless, molecular diagnosis of early-onset ion channel disorders is having an immediate clinical and translational impact in neurology. Causative gene discoveries are widely embraced by clinicians eager to genetically tag and stratify affected individuals, parse their neurological syndromes, and select appropriate pharmacology according to the lost or acquired conductance of the mutated channel. In parallel, they are forging the creation of parent–scientist advocacy groups focused on ion channel research, bioinformatics tools to evaluate variant pathogenicity, relational patient variant database websites that link treating physicians with expert channel physiologists Ion channel genes, originally implicated in inherited excitability disorders of muscle and heart, have captured a major role in the molecular diagnosis of central nervous system disease. Their arrival is heralded by neurologists confounded by a broad phenotypic spectrum of early-onset epilepsy, autism, and cognitive impairment with few effective treatments. As detection of rare structural variants in channel subunit proteins becomes routine, it is apparent that primary sequence alone cannot reliably predict clinical severity or pinpoint a therapeutic solution. Future gains in the clinical utility of variants as biomarkers integral to clinical decision making and drug discovery depend on our ability to unravel complex developmental relationships bridging single ion channel structure and human physiology. Precision physiology and rescue of brain ion channel disorders