F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Exp Neurol. 2023 Jun;364:114393. doi: 10.1016/j.expneurol.2023.114393. Epub 2023 Mar 30.
Gain-of-function mutations in Scn9a, which encodes the peripheral sensory neuron-enriched voltage-gated sodium channel Na1.7, 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 Na1.7 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 Na1.7 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.
Scn9a 基因中的功能获得性突变，该基因编码外周感觉神经元丰富的电压门控钠离子通道 Na1.7，导致阵发性极痛障碍 (PEPD)、遗传性红斑性肢痛症 (IEM) 和小纤维神经病 (SFN)。相反，该基因的功能丧失性突变与先天性无痛症 (CIP) 有关。这些突变为钠离子通透性改变和神经元兴奋性导致躯体感觉异常、疼痛或丧失之间的联系提供了证据。我们之前在携带 Na1.7 功能获得性突变（I228M）的年轻成年小鼠中的研究工作表明，预期的 DRG 神经元过度兴奋，但出人意料的是，这些小鼠对机械和热行为的敏感性正常。我们现在表明，随着年龄的增长，具有这种突变的雄性和雌性小鼠出人意料地对有害热和冷变得非常不敏感，以及跨越全身的皮肤损伤。电生理学表明，与年轻小鼠相比，年老的 I228M 小鼠 DRG 钠离子通透性显著丧失，激活和缓慢失活动力学发生变化，代表功能丧失。通过 RNA 测序，我们探讨了这些与年龄相关的变化如何产生表型变化，发现与 C-低阈值机械感受器相关的基因表达显著且特异性下降，表明这种 DRG 神经元亚型可能对 Na1.7 功能障碍表型有潜在贡献。因此，电压门控通道中的功能获得性突变可以在较长时间内导致神经系统发生高度复杂和意外的改变，超出兴奋性变化。
