WHY DO MUTATIONS IN IKBKAP CAUSE FAMILIAL DYSAUTONOMIA?

为什么 IKBKAP 突变会导致家族性自主神经失调？

• 批准号: 8916840
• 负责人: Frances Lefcort
• 金额: $ 32.88万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916840
• 关键词: 3' Splice Site; Adrenal Medulla; Adult; Age; Age-Months; Apoptosis; Apoptotic; Ataxia; Ataxic Gait; Autonomic Nervous System Part; Autonomic nervous system; Axon; Axonal Transport; Birth; Blindness; Cells; Cessation of life; Complex; Degenerative Disorder; Development; Disease; Dorsal; Dysautonomias; Endocytosis; Esthesia; Exhibits; Failure; Familial Dysautonomia; Functional disorder; Fungiform Papilla; Gait Ataxia; Genes; Genetic Transcription; Goals; Health; Heart Arrest; Hereditary Disease; Hereditary Sensory Neuropathy; Homeostasis; Human; Hypothalamic structure; Kidney Failure; Knockout Mice; Lead; Limb structure; Lung; Messenger RNA; Mitotic; Modeling; Motor; Motor Neurons; Movement; Mus; Muscle; Musculoskeletal; Mutation; Nervous system structure; Neural Crest; Neural Crest Cell; Neuraxis; Neuromuscular Junction; Neurons; Nonsense-Mediated Decay; Organ; Orthostatic Hypotension; Pain; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Play; Pneumonia; Positioning Attribute; Post-Translational Protein Processing; Presynaptic Terminals; Proteins; Role; Sensory; Signal Transduction; Spinal Cord; Stem cells; Sudden Death; Sympathetic Ganglia; Symptoms; Synaptic Transmission; Syncope; System; Tachycardia; Temperature; Temperature Sense; Testing; Therapeutic; Unconscious State; Unsteady Gait; Vomiting; arm; autonomic neuropathy; blood pressure regulation; foot; gene function; human disease; motor impairment; mouse model; nerve supply; neuronal cell body; neurotransmission; neurotrophic factor; novel; prevent; progenitor; protein function; response; retrograde transport; scoliosis; spinal nerve posterior root; vasculogenesis

DESCRIPTION (provided by applicant): The goal of this proposal is to understand why reductions in the level of the IKAP protein cause the Hereditary Sensory and Autonomic Neuropathy Type III, Familial Dysautonomia (FD; also called Riley Day Syndrome). This disease is both a developmental and a progressive disorder. It is marked by tachycardia, orthostatic hypotension which results in frequent fainting and autonomic vomiting "crises", pulmonary problems, renal failure and musculoskeletal manifestations including scoliosis, ataxia and weakness. This disease not only devastates the functioning of the Autonomic Nervous System, but also is marked by severe deficits in pain and temperature sensation and has CNS manifestations. FD is due to a mutation in the gene IKBKAP, in a splice acceptor site (IVS20+6T>C; 99.5% of patients) that causes the transcription of a truncated mRNA which is targeted for nonsense-mediated decay. The function of the encoded protein, IKAP, is unresolved. It clearly plays an essential role in that mice that are completely null for Ikbkap die by E10 due to failure in neurulation and vasculogenesis. To determine what role IKAP serves in the nervous system and why its absence results in FD, we have made 2 conditional-knock out mouse models for the disease in which Ikbkap is deleted either from the neural crest (using a Wnt1-cre), or from neurons in the central nervous system (CNS), but not the peripheral nervous system (PNS; using a Ta1tubulin-cre). The Wnt1-cre/Ikbkap mice die within 24 hrs of birth and analyses of their PNS demonstrates a recapitulation of the human disease with significant reductions in sympathetic, parasympathetic and TrkA+ pain and temperature sensing neurons and thus provides an excellent model for determining the developmental disruptions in the disease. We found that the reduction in PNS neurons during development is due to apoptosis of both progenitor cells and post-mitotic neurons. The Ta1tubulin-cre/Ikbkap also faithfully recapitulates classic, but distinct, hallmarks of FD including scoliosis, hind limb weakness, and gait ataxia. These mice die on average at 5 months and their condition degenerates as they age, thus they provide an excellent system in which to study the progressively degenerative mechanisms that mark FD. These results indicate not only is deletion of Ikbkap in the nervous system sufficient to cause FD, but that we have two independent models in which we can dissect the functions of IKAP in the CNS and PNS, during development vs. progression in the adult. Since the Autonomic Nervous system (ANS) is a circuit that includes both CNS and PNS components, we propose here to take a system wide approach to determine the function of IKAP in both the CNS and PNS. With an understanding of the key pathways which require IKAP, the long term goal is to develop strategies to prevent the progressive degeneration of both CNS and PNS neurons in FD and the other HSANs.

描述（由申请人提供）：本提案的目的是了解为什么 IKAP 蛋白水平降低会导致 III 型遗传性感觉和自主神经病、家族性自主神经功能障碍（FD；也称为莱利·戴综合症）。这种疾病既是一种发育性疾病，又是一种进行性疾病。其特点是心动过速、直立性低血压（导致频繁昏厥和自主呕吐“危机”）、肺部问题、肾衰竭和肌肉骨骼表现，包括脊柱侧凸、共济失调和虚弱。这种疾病不仅破坏自主神经系统的功能，而且以疼痛和温度感觉严重缺失为特征，并具有中枢神经系统表现。 FD 是由于剪接受体位点 IKBKAP 基因的突变（IVS20+6T>C；99.5% 的患者）导致截短 mRNA 的转录，该 mRNA 的目标是无义介导的衰变。所编码的蛋白质 IKAP 的功能尚未解决。它显然在 Ikbkap 完全无效的小鼠死亡中发挥着重要作用 由于神经形成和血管生成失败而导致E10。为了确定 IKAP 在神经系统中的作用以及为什么它的缺失会导致 FD，我们针对该疾病制作了 2 个条件敲除小鼠模型，其中 Ikbkap 被从神经嵴（使用 Wnt1-cre）或中枢神经系统（CNS）神经元中删除，但不从周围神经系统（PNS；使用 Ta1tubulin-cre）中删除。 Wnt1-cre/Ikbkap 小鼠在出生 24 小时内死亡，对其 PNS 的分析表明，交感神经、副交感神经和 TrkA+ 疼痛和温度感知神经元显着减少，从而再现了人类疾病，从而为确定该疾病的发育障碍提供了一个极好的模型。我们发现发育过程中三七总皂苷神经元的减少是由于祖细胞和有丝分裂后神经元的凋亡所致。 Ta1tubulin-cre/Ikbkap 还忠实地再现了 FD 的经典但独特的特征，包括脊柱侧凸、后肢无力和步态共济失调。这些小鼠平均在 5 个月内死亡，并且它们的状况随着年龄的增长而退化，因此它们提供了一个极好的系统来研究 FD 的渐进退化机制。这些结果表明，不仅神经系统中 Ikbkap 的缺失足以引起 FD，而且我们有两个独立的模型，可以在成人的发育与进展过程中剖析 IKAP 在 CNS 和 PNS 中的功能。由于自主神经系统 (ANS) 是一个包含 CNS 和 PNS 组件的回路，因此我们在此建议采用系统范围的方法来确定 IKAP 在 CNS 和 PNS 中的功能。了解需要 IKAP 的关键途径后，长期目标是制定策略来防止 FD 和其他 HSAN 中 CNS 和 PNS 神经元进行性退化。