1 Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
2 Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT, USA.
Mol Pain. 2019 Jan-Dec;15:1744806919849802. doi: 10.1177/1744806919849802.
Diabetes mellitus is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy is one of the most common. A substantial number of patients with diabetic peripheral neuropathy develop chronic pain, but the genetic and epigenetic factors that predispose diabetic peripheral neuropathy patients to develop neuropathic pain are poorly understood. Recent targeted genetic studies have identified mutations in α-subunits of voltage-gated sodium channels (Nas) in patients with painful diabetic peripheral neuropathy. Mutations in proteins that regulate trafficking or functional properties of Nas could expand the spectrum of patients with Na-related peripheral neuropathies. The auxiliary sodium channel β-subunits (β1-4) have been reported to increase current density, alter inactivation kinetics, and modulate subcellular localization of Na. Mutations in β-subunits have been associated with several diseases, including epilepsy, cancer, and diseases of the cardiac conducting system. However, mutations in β-subunits have never been shown previously to contribute to neuropathic pain. We report here a patient with painful diabetic peripheral neuropathy and negative genetic screening for mutations in SCN9A, SCN10A, and SCN11A-genes encoding sodium channel α-subunit that have been previously linked to the development of neuropathic pain. Genetic analysis revealed an aspartic acid to asparagine mutation, D109N, in the β2-subunit. Functional analysis using current-clamp revealed that the β2-D109N rendered dorsal root ganglion neurons hyperexcitable, especially in response to repetitive stimulation. Underlying the hyperexcitability induced by the β2-subunit mutation, as evidenced by voltage-clamp analysis, we found a depolarizing shift in the voltage dependence of Na1.7 fast inactivation and reduced use-dependent inhibition of the Na1.7 channel.
糖尿病是一种全球性的挑战，有许多不同的健康后果，其中糖尿病周围神经病变是最常见的一种。相当数量的糖尿病周围神经病变患者会发展为慢性疼痛，但导致糖尿病周围神经病变患者易患神经病理性疼痛的遗传和表观遗传因素仍知之甚少。最近的靶向基因研究已经在患有痛性糖尿病周围神经病变的患者中发现了电压门控钠离子通道（Nas）的α亚基突变。调节 Nas 转运或功能特性的蛋白质突变可能会扩大与 Na 相关的周围神经病变患者的范围。辅助钠离子通道β亚基（β1-4）已被报道能增加电流密度、改变失活动力学，并调节 Na 的亚细胞定位。β亚基的突变与几种疾病有关，包括癫痫、癌症和心脏传导系统疾病。然而，β亚基的突变以前从未被证明与神经病理性疼痛有关。我们在此报告一例痛性糖尿病周围神经病变患者，其 SCN9A、SCN10A 和 SCN11A 基因（编码先前与神经病理性疼痛发展相关的钠离子通道 α 亚基）的遗传筛查均为阴性。基因分析显示β2 亚基的天冬氨酸到天冬酰胺突变，D109N。使用电流钳进行的功能分析显示，β2-D109N 使背根神经节神经元过度兴奋，特别是对重复刺激的反应。电压钳分析证实，β2 亚基突变诱导的超兴奋性，我们发现 Na1.7 快速失活的电压依赖性和 Na1.7 通道的使用依赖性抑制作用减弱。
