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)：本提案的目标是了解为什么IKAP蛋白水平的降低会导致遗传性感觉和自主神经病变III型，家族性自主神经障碍(FD；也称为Riley Day综合征)。这种疾病既是一种发育障碍，也是一种进行性疾病。它的特点是心动过速、直立性低血压导致频繁晕厥和自主神经呕吐“危象”、肺部问题、肾功能衰竭和肌肉骨骼表现，包括脊柱侧弯、共济失调和虚弱。这种疾病不仅破坏自主神经系统的功能，而且以严重的疼痛和温度感觉障碍为特征，并有中枢神经系统的表现。FD是由于剪接受体(IVS20+6T&GT；C；99.5%的患者)上的IKBKAP基因突变引起的，该突变导致截短的mRNA转录，该转录是无义介导的衰退的目标。编码蛋白IKAP的功能尚未解决。显然，它在Ikbkap完全为零小鼠死亡过程中起着至关重要的作用 由于神经形成和血管生成失败而被E10感染。为了确定IKAP在神经系统中起什么作用以及为什么它的缺失会导致FD，我们制作了两种条件敲除小鼠的疾病模型，在这些模型中，Ikbkap要么从神经脊(使用WNT1-cre)删除，要么从中枢神经系统(CNS)的神经元中删除，但不从外周神经系统(PNS；使用Ta1tuBulin-cre)删除。WNT1-cre/Ikbkap小鼠出生后24小时内死亡，对它们的PNS的分析表明，交感、副交感和TrkA+痛温感觉神经元显著减少，这是人类疾病的重演，因此为确定疾病的发育障碍提供了一个极好的模型。我们发现，PNS神经元在发育过程中的减少是由于前体细胞和有丝分裂后神经元的凋亡所致。Ta1tuBulin-cre/Ikbkap也忠实地概括了FD的经典但独特的特征，包括脊柱侧弯、后肢无力和步态共济失调。这些小鼠平均死亡5个月，它们的状况随着年龄的增长而退化，因此它们提供了一个很好的系统来研究标志着FD的渐进性退化机制。这些结果表明，不仅神经系统中Ikbkap的缺失足以导致FD，而且我们有两个独立的模型，在其中我们可以剖析IKAP在中枢和三叉神经节中的功能，在成人的发育和发展过程中。由于自主神经系统(ANS)是一个同时包括CNS和PNS组件的电路，我们建议采取系统范围的方法来确定IKAP在CNS和PNS中的功能。随着对需要IKAP的关键通路的了解，长期目标是开发策略来防止FD和其他HSAN中CNS和PNS神经元的进行性退化。