KCNQ variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience. Issue 3 (8th September 2021)

• Record Type: Journal Article
• Authors: Yuan, Jun-Hui; Estacion, Mark; Mis, Malgorzata A; Tanaka, Brian S; Schulman, Betsy R; Chen, Lubin; Liu, Shujun; Dib-Hajj, Fadia B; Dib-Hajj, Sulayman D; Waxman, Stephen G
• Is Part Of: Brain communications. Volume 3:Issue 3(2021)
• Publication Date: 2021-09-08
• Subjects: Erythromelalgia -- induced pluripotent stem cells -- pain -- potassium channel -- whole-exome sequencing; 616
• DOI: 10.1093/braincomms/fcab212
• Languages: English
• ISSNs: 2632-1297

Abstract

Abstract: There is a pressing need for understanding of factors that confer resilience to pain. Gain-of-function mutations in sodium channel Nav1.7 produce hyperexcitability of dorsal root ganglion neurons underlying inherited erythromelalgia, a human genetic model of neuropathic pain. While most individuals with erythromelalgia experience excruciating pain, occasional outliers report more moderate pain. These differences in pain profiles in blood-related erythromelalgia subjects carrying the same pain-causative Nav1.7 mutation and markedly different pain experience provide a unique opportunity to investigate potential genetic factors that contribute to inter-individual variability in pain. We studied a patient with inherited erythromelalgia and a Nav1.7 mutation (c.4345T>G, p. F1449V) with severe pain as is characteristic of most inherited erythromelalgia patients, and her mother who carries the same Nav1.7 mutation with a milder pain phenotype. Detailed six-week daily pain diaries of pain episodes confirmed their distinct pain profiles. Electrophysiological studies on subject-specific induced pluripotent stem cell-derived sensory neurons from each of these patients showed that the excitability of these cells paralleled their pain phenotype. Whole-exome sequencing identified a missense variant (c.2263C>T, p. D755N) in KCNQ3 (Kv7.3) in the pain resilient mother. Voltage-clamp recordings showed that co-expression of Kv7.2-wild type (WT)/Kv7.3-D755N channels produced larger M-currents than that of Kv7.2-WT/Kv7.3-WT. The difference in excitability of the patient-specific induced pluripotent stem cell-derived sensory neurons was mimicked by modulating M-current levels using the dynamic clamp and a model of the mutant Kv7.2-WT/Kv7.3-D755N channels. These results show that a 'pain-in-a-dish' model can be used to explicate genetic contributors to pain, and confirm that KCNQ variants can confer pain resilience via an effect on peripheral sensory neurons. Abstract : Yuan et al. report that a missense variant in KCNQ3 gene, detected by whole-exome sequencing, contributes to phenotypic diversity of a daughter–mother pair of patients with inherited erythromelalgia. They propose the usefulness of patient-specific induced pluripotent stem cell-derived sensory neurons for studies on heterogeneity of pain and resilience to pain. Graphical Abstract: