About this Research Topic
Mutations in sodium channel genes of excitable tissues such as nerve and muscle produce inheritable or spontaneous channelopathy syndromes. Sodium channelopathies present with an array of gain-of-function and loss-of-function phenotypic syndromes in brain, peripheral nerve, cardiac and skeletal muscle. Identification of the mutations associated with patients exhibiting a specific disease phenotype is often followed by functional characterization of the effects of these mutations on channel gating. These studies provide a mechanistic explanation of genotype to phenotype relations, and have greatly facilitated our understanding of structural determinants and pharmacology of voltage-gated ion channels.
Advances in the molecular approaches to identify disease variants have greatly expanded the list of candidate genes and mutations that may be causal to specific patient syndromes. These include the use of next generation sequencing and algorithms to predict the effect of specific mutations as benign or pathogenic, helping to focus functional characterization on variants most likely to be determinants of the pathogenesis of disease. There is an emerging direction in channelopathy investigation to determine the impact of these mutations at the tissue and organismal level with the use of transgenic animals and CRISPR/Cas9 gene editing, and at the cellular level with pluripotent stem cells, computational and mathematical approaches. Taken together with clinical work, these studies expand the investigation of the pharmacological alleviation of phenotype from patient, to tissue, to cell.
The important long-term goal is to investigate the determination of causality of specific biophysical defects towards specific disease phenotypes. This goal is presented by the challenge that disease phenotypes may be the consequence of multiple factors including the defects provided by several ion channel genes. Single mutations may also produce defects consistent with multiple disease phenotypes. Finally, understanding the effects of ion channel defects on membrane excitability as determined from functional characterization in a diversity of expression systems represents a challenge for computational and mathematical approaches.
The aim of this Research Topic is to address these challenges using functional, structural and computational information gained in channelopathy studies towards the development of pharmacological or other therapeutic strategies. We welcome submissions of Original Research, Reviews, Methods and Mini Reviews to provide a more comprehensive view of the diversity of ion channel mutations associated with patient phenotypes, and new approaches to study the impact of these mutations at the tissue and organismal level. Topics of interest include:
• Mixed phenotype and overlap syndrome channelopathy mutations
• Genomic sequencing and algorithms to identify and predict disease association for ion channel mutations
• Transgenic and pluripotent stem cell approaches to channelopathies and their pharmacology
• Computational approaches towards an understanding of the relationship of biophysical and pharmacological profiles in channelopathies.
• Insight into channelopathies revealed by the study of prokaryotic ion channels
Keywords: Channelopathy syndromes, mixed phenotype, sodium channelopathies, genomic sequencing, computational pharmacology, prokaryotic ion channels
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