Loss, Gain and Altered Function of Ligand-Gated Ion Channels in Neurological Disorders – Defining Routes to Personalised Medicines

Ligand-gated ion channels activated by acetylcholine, GABA, glycine, glutamate and serotonin play a key role in health and disease. In recent years, the advent of next-generation sequencing technologies has resulted in an explosion of new sequence variants in the LGIC genes linked to human neurological disorders, including autism spectrum disorder, developmental delay, epilepsy, intellectual disability, and startle disease. However, currently genetic and bioinformatics approaches cannot tell us whether a given gene variant represents a loss, gain or alteration of function, nor inform us about potential treatment pathways for affected individuals. While many inherited or de novo mutations fall into classic loss-of-function categories, e.g. defective trafficking, loss of agonist binding efficacy, detailed functional analyses are yielding new insights into disease mechanisms. These include mutations that induce gain-of-function, or altered function – e.g. leak currents, changes in voltage rectification and ion permeation.

Whilst these disorders may be individually rare, understanding disease mechanisms is vital, as it can lead to an accurate diagnosis, genetic counselling and guide personalised treatment plans. In this special topic, we encourage original research or methods papers, reviews, commentaries, or perspectives that highlight how detailed functional characterisation of genetic ligand-gated ion channel mutations increases our understanding of ion channel function, neurological disorders and/or defines avenues for the development of personalised medicines.

Studies reporting the functional characterisation of new disease-associated variants in receptors for acetylcholine (ACh), GABA, glycine, glutamate (e.g. NMDA, AMPA, kainate receptors) or serotonin with accompanying functional data will be considered. In addition, studies using computational, molecular, cellular, and whole-organism models to uncover the molecular mechanisms of disease-causing sequence variants in ligand-gated ion channels are within scope.