Scn9a中的功能增益突变,编码外周感觉神经元富集电压门控钠通道Nav1.7,引起阵发性极端疼痛障碍(PEPD),遗传性红血病(IEM),和小纤维神经病变(SFN)。相反,基因中的功能缺失突变与先天性疼痛不敏感(CIP)有关.这些突变是钠电导改变和神经元兴奋性之间联系的证据,导致体感畸变。疼痛,或它的损失。我们以前在具有Nav1.7功能增益突变的成年小鼠中进行的工作,I228M,显示了预期的DRG神经元过度兴奋,但出乎意料的是,小鼠具有正常的机械和热行为敏感性。我们现在表明,随着这种突变的雄性和雌性小鼠的衰老,出乎意料地对有害的热和冷产生了深刻的不敏感,以及跨越身体的皮肤损伤。电生理学证明,与年轻的老鼠相反,老年I228M小鼠DRGs钠电导严重丧失,激活和缓慢失活动力学发生变化,表示功能丧失。通过RNA测序,我们探索了这些与年龄相关的变化如何产生表型变化,并发现了C低阈值机械受体(cLTMR)相关基因表达的显着和特异性降低。提示该DRG神经元亚型对Nav1.7功能障碍表型的潜在贡献。因此,电压门控通道中的GOF突变可以在延长的时间内产生,神经系统的高度复杂和意想不到的变化超出了兴奋性的变化。
Gain-of-function mutations in Scn9a, which encodes the peripheral sensory neuron-enriched voltage-gated sodium channel Nav1.7, cause paroxysmal extreme pain disorder (PEPD), inherited erythromelalgia (IEM), and small fiber neuropathy (SFN). Conversely, loss-of-function mutations in the gene are linked to congenital insensitivity to pain (CIP). These mutations are evidence for a link between altered sodium conductance and neuronal excitability leading to somatosensory aberrations, pain, or its loss. Our previous work in young adult mice with the Nav1.7 gain-of-function mutation, I228M, showed the expected DRG neuron hyperexcitability, but unexpectedly the mice had normal mechanical and thermal behavioral sensitivity. We now show that with aging both male and female mice with this mutation unexpectedly develop a profound insensitivity to noxious heat and cold, as well skin lesions that span the body. Electrophysiology demonstrates that, in contrast to young mice, aged I228M mouse DRGs have a profound loss of sodium conductance and changes in activation and slow inactivation dynamics, representing a loss-of-function. Through RNA sequencing we explored how these age-related changes may produce the phenotypic changes and found a striking and specific decrease in C-low threshold mechanoreceptor- (cLTMR) associated gene expression, suggesting a potential contribution of this DRG neuron subtype to Nav1.7 dysfunction phenotypes. A GOF mutation in a voltage-gated channel can therefore produce over a prolonged time, highly complex and unexpected alterations in the nervous system beyond excitability changes.