Correction of sodium channel mutations in sensory neurons reverses aberrant properties

Abstract

Inherited erythromelalgia, small fiber neuropathy and paroxysmal extreme pain disorder are caused by gain-of-function mutations in the voltage gated sodium channel Nav1.7. How different mutations in the same channel enhancing electrogenesis in sensory neurons results in such distinct disease presentations remains unknown. Most of the work analysing the impact of these mutations on electrophysiological properties has utilized over-expression systems in cell lines and rodent sensory neurons, which may differ from the natural context. We have differentiated sensory neurons from iPSCs derived from patient samples that have the Nav1.7 A1632G mutation. This strategy reveals changes in electrophysiological properties not previously observed in cell lines, that may be important for disease presentation. Further, using CRISPR/Cas9, we corrected this mutation which reduced the underlying hyperexcitability, providing a path for personalized medicine to treat these disorders and introduced the mutation into control iPSCs which generated hyperexcitability providing causality. iPSC sensory neurons are a robust, scalable, and relevant model to study the effects of gain-of-function mutations in ion channels in pain-related disorders.