Sodium channel mutations as a possible cause for primary dysautonomia

项目总结 原发性自主神经异常(PD)不同于家族性自主神经异常，是一种多因素疾病 这是在自主神经系统(ANS)功能不正常的家庭中运行的，导致 一系列致残性疾病症状。尽管帕金森病表现出孟德尔式的遗传模式， 潜在的遗传起源尚未确定。治疗完全基于缓解症状。 而且也没有治愈的理由。帮助填补这一知识缺口，并开始确定贡献 影响帕金森病的因素，我们密切跟踪了69个家系，这些家系的遗传方式以孟德尔多胎为主 共同症状包括：(一)慢性立位不耐受，(二)慢性疲劳，(三)主要病灶 多汗症、(Iv)慢性瘙痒和(V)广泛性焦虑。我们启动了全外显子组测序 这些家系中的先证者的结果数据表明帕金森病和一种 电压门控钠(NAV)通道基因突变的常染色体显性遗传模式。 我们用NAV通道调节剂治疗家庭成员的事实加强了这一结果 这解决了他们的许多投诉。根据初步结果，我们假设看起来 病理生理学联系弥漫性自主神经症状，是一种NAV通道突变可以 将ANS转变为过度敏感的神经系统，随着时间的推移，它会发展成丧失能力和持久性 疾病。为了开始研究NAV通道突变在帕金森病中的作用，我们设计了一种策略来帮助 阐明我们的靶点与患者交感神经系统异常激活之间的联系。 我们的方法最终将创建一种经过验证的具有自主神经功能障碍的动物模型 人类疗法是可以测试的。成功的完成将为帕金森病的遗传原因提供新的见解， 这是了解这种疾病的多因素性质的关键一步。

PROJECT SUMMARY Primary Dysautonomia (PD), distinct from the entity called familial dysautonomia, is a multifactorial condition that runs in families in which the autonomic nervous system (ANS) does not function correctly leading to a range of disabling disease symptoms. Despite the known fact that PD exhibits Mendelian inheritance patterns, underlying genetic origins have not been identified. Treatments are solely based on alleviating symptomatology and there is no rationale for effectuating a cure. To help fill this knowledge gap and start identifying contributing factors to PD, we closely followed sixty-nine families with a dominant Mendelian inheritance pattern of multiple shared symptoms including (i) chronic orthostatic intolerance, (ii) chronic fatigue, (iii) primary focal hyperhidrosis, (iv) chronic itch, and (v) generalized anxiety. We initiated whole-exome sequencing (WES) of the probands in these families with resulting data suggesting a causal relationship between PD and an autosomal dominant inheritance pattern of mutations in genes encoding voltage-gated sodium (NaV) channels. This outcome is strengthened by the fact that we have treated family members with NaV channel modulators which resolved many of their complaints. Based on preliminary results, we hypothesize that what appears to pathophysiologically link diffuse autonomic symptoms, is a disease model in which NaV channel mutations can transform the ANS into an oversensitive nervous system that over time develops incapacitating and persistent disease. To start investigating the involvement of NaV channel mutations in PD, we devised a strategy to help elucidate the link between our targets and anomalous activation of the sympathetic nervous system in patients. Our approach will culminate in the creation of a validated animal model with autonomic dysfunction in which human therapeutics can be tested. Successful completion will provide new insights into genetic causes of PD, a vital step towards understanding the multifactorial nature of this disorder.