Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.
Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy.
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DOI：
10.1097/j.pain.0000000000001116
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发表时间：
2018-03
期刊：
影响因子：
7.4
通讯作者：
Bennett DLH
中科院分区：
文献类型：
--
作者：
Blesneac I;Themistocleous AC;Fratter C;Conrad LJ;Ramirez JD;Cox JJ;Tesfaye S;Shillo PR;Rice ASC;Tucker SJ;Bennett DLH
补充数字内容在文本中可用。罕见的NaV1.7变异与糖尿病周围神经病变患者神经性疼痛的发生相关。糖尿病周围神经病变（DPN）是糖尿病常见的致残性并发症。几乎一半的DPN患者发生神经性疼痛（NeuP），目前的镇痛治疗是不够的。了解遗传变异在疼痛性DPN发生中的作用，有助于更好地了解疼痛发病机制，以便在临床试验中更好地对患者进行分层，并更适当地进行靶向治疗。在这里，我们研究了电压门控钠通道NaV1.7和NeuP的变异体在DPN患者的深度表型队列中的关系。虽然在78名无痛性DPN参与者中没有发现罕见变异，但我们在10名（共111名）疼痛性DPN参与者中发现了12种罕见的NaV1.7变异。其中5种变异先前已在其他NeuP疾病的背景下描述，7种先前未与NeuP相关。那些罕见变异的患者报告了更严重的疼痛和更大的敏感性，对压力刺激的定量感觉测试。2个新的变体（M1852 T和T1596 I）的电生理特性表明，增益的功能变化的结果，明显受损的通道快速失活。使用NaV1.7的结构模型，我们还能够进一步深入了解快速失活的结构机制以及C-末端结构域在此过程中的作用。我们的观察结果表明，罕见的NaV1.7变异有助于DPN患者发生NeuP。它们的鉴定有助于理解感觉表型、患者分层，并有助于有效的靶向治疗。
Supplemental Digital Content is Available in the Text. Rare NaV1.7 variants are associated with the development of neuropathic pain in patients with diabetic peripheral neuropathy. Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel NaV1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare NaV1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of NaV1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare NaV1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively.
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影响因子：
2.1
作者：
Calloe, Kirstine;Schmitt, Nicole;Antzelevitch, Charles
通讯作者：
Antzelevitch, Charles
影响因子：
3.7
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作者：
Han, C.;Hoeijmakers, J. G. J.;Waxman, S. G.
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Waxman, S. G.
影响因子：
11.2
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通讯作者：
Merkies, Ingemar S. J.
影响因子：
16.2
作者：
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通讯作者：
Boulton AJ