Sodium channel mutations as a possible cause for primary dysautonomia

钠通道突变可能是原发性自主神经功能障碍的原因

基本信息

批准号：
10586393
负责人：
MALCOLM V BROCK
金额：
$ 53.08万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586393
关键词：
Ablation Action Potentials Adopted Affect Amino Acid Substitution Animal Model Animals Arrhythmia Autonomic Dysfunction Autonomic nervous system Baroreflex Behavior Biophysics Cardiac Cells Cervical Chest Chromosome 9 Chronic Chronic Orthostatic Intolerance Circadian Rhythms Clinical Data Diffuse Disease Disease model Dysautonomias Electrophysiology (science)Exhibits Familial Dysautonomia Family Family member Fatigue Genes Genetic Hormonal Human Hyperhidrosis disorder Immunologics Inheritance Patterns Knowledge Link Measures Membrane Methods Microscopy Modeling Monitor Movement Mus Mutation Nature Nervous System Neurons Outcome Pathogenesis Patients Pharmacological Treatment Phenotype Play Pruritus RNA Splicing Reporting Role Running Severities Site Sodium Sodium Channel Spinal Ganglia Stimulus Sweating Sympathetic Ganglia Sympathetic Nervous System Symptoms System Testing Therapeutic Time Variant autosome behavior test chronic itch clinically relevant disabling disease drug testing exome sequencing experimental study generalized anxiety insight mouse model mutant patch clamp proband reduce symptoms segregation sensory stimulus somatosensory symptomatology trafficking transcription factor voltage

项目摘要

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.

项目概要原发性自主神经功能障碍 (PD) 与家族性自主神经功能障碍不同，是一种多因素病症家族中的自主神经系统（ANS）无法正常运作，导致一系列致残疾病症状。尽管众所周知 PD 表现出孟德尔遗传模式，潜在的遗传起源尚未确定。治疗仅基于缓解症状并且没有实现治愈的理由。为了帮助填补这一知识空白并开始确定贡献 PD 的因素，我们密切关注了 69 个具有多种孟德尔遗传模式的家庭。共同症状包括（i）慢性直立不耐受，（ii）慢性疲劳，（iii）原发性局灶性多汗症，(iv) 慢性瘙痒，以及 (v) 广泛性焦虑。我们启动了全外显子组测序（WES）这些家庭中的先证者，所得数据表明 PD 与先证者之间存在因果关系编码电压门控钠 (NaV) 通道的基因突变的常染色体显性遗传模式。我们用 NaV 通道调制器治疗家庭成员这一事实强化了这一结果这解决了他们的许多投诉。根据初步结果，我们假设病理生理学上将弥漫性自主神经症状联系起来，是一种疾病模型，其中 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，该系统会变得丧失能力并持续存在疾病。为了开始研究 NaV 通道突变与 PD 的关系，我们设计了一种策略来帮助阐明我们的目标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个经过验证的具有自主神经功能障碍的动物模型，其中可以测试人类疗法。成功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重要一步。