KCNQ variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience.
KCNQ variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience.
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DOI：
10.1093/braincomms/fcab212
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发表时间：
2021
影响因子：
4.8
通讯作者：
Waxman SG
中科院分区：
文献类型：
--
作者：
Yuan JH;Estacion M;Mis MA;Tanaka BS;Schulman BR;Chen L;Liu S;Dib-Hajj FB;Dib-Hajj SD;Waxman SG
我们迫切需要了解那些赋予我们抗痛能力的因素。钠通道Nav1.7的功能获得突变可导致背根神经节神经元的高兴奋性，这是遗传性红斑性肢痛症的一种人类神经性疼痛遗传模型。虽然大多数红斑性肢痛症患者会经历剧烈的疼痛，但偶尔也有例外，他们会报告更中度的疼痛。携带相同的疼痛致病基因Nav1.7突变和明显不同的疼痛经历的血液相关性红斑性痛症受试者的疼痛谱差异为研究导致个体间疼痛差异的潜在遗传因素提供了独特的机会。我们研究了一名遗传性红斑性肢痛症和Nav1.7突变（c.4345T>G, p. F1449V）的患者，其剧烈疼痛是大多数遗传性红斑性肢痛症患者的特征，而她的母亲携带相同的Nav1.7突变，疼痛表型较轻。详细的六周每日疼痛日记证实了他们独特的疼痛特征。对这些患者的特异性诱导多能干细胞衍生的感觉神经元的电生理研究表明，这些细胞的兴奋性与他们的疼痛表型相似。全外显子组测序鉴定了疼痛恢复母亲的KCNQ3 （Kv7.3）错义变体（c.2263C>T, p. D755N）。电压钳记录显示，共表达kv7.2 -野生型(WT)/Kv7.3-D755N通道产生的m电流大于Kv7.2-WT/Kv7.3-WT通道。利用动态箝位和Kv7.2-WT/Kv7.3-D755N突变通道模型，通过调节m电流水平来模拟患者特异性诱导的多能干细胞来源的感觉神经元的兴奋性差异。这些结果表明，“盘子里的疼痛”模型可以用来解释疼痛的遗传因素，并证实KCNQ变异可以通过对周围感觉神经元的影响来赋予疼痛弹性。Yuan等人报道，通过全外显子组测序检测到KCNQ3基因的错义变异，导致了一对母女遗传性红斑性肢痛症患者的表型多样性。他们提出了患者特异性诱导多能干细胞衍生的感觉神经元对疼痛异质性和疼痛恢复力研究的有用性。
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. 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.
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影响因子：
14.5
作者：
Labau, Julie I. R.;Estacion, Mark;Waxman, Stephen G.
通讯作者：
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通讯作者：
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