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

• 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
• 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

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.

项目摘要 原发性自主神经功能障碍（PD）是一种多因素的疾病，与家族性自主神经功能障碍不同 在自主神经系统（ANS）功能不正常的家庭中， 一系列致残性疾病症状。尽管已知PD表现出孟德尔遗传模式， 潜在的遗传起源尚未确定。治疗仅基于缓解炎症 也没有理由进行治疗为了帮助填补这一知识空白，并开始确定贡献 我们密切跟踪了69个具有多重显性孟德尔遗传模式的家庭， 共有症状包括（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，和（v）广泛性焦虑。我们启动了全外显子组测序（WES）， 这些家族中的先证者，其结果数据表明PD与 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通道调节剂治疗家族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， 在病理生理学上联系弥漫性自主神经症状，是一种疾病模型，其中NaV通道突变可以 将ANS转化为过度敏感的神经系统，随着时间的推移， 疾病为了开始研究NaV通道突变在PD中的参与，我们设计了一种策略来帮助 阐明我们的目标和患者交感神经系统异常激活之间的联系。 我们的方法最终将建立一个有效的自主神经功能障碍动物模型， 可以测试人类治疗剂。成功完成将为PD的遗传原因提供新的见解， 这是理解这种疾病多因素本质的重要一步。