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: 8668713
• 负责人: Frances Lefcort
• 金额: $ 31.5万
• 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/8668713
• 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; Heart Arrest; Hereditary Disease; Hereditary Sensory Neuropathy; Homeostasis; Human; Hypothalamic structure; Impairment; 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; mouse model; nerve supply; neuronal cell body; neurotransmission; neurotrophic factor; novel; prevent; progenitor; protein function; public health relevance; 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遗传性感觉和自主神经病III型，家族性自主神经功能障碍（FD;也称为Riley Day综合征）。这种疾病既是一种发展性疾病，也是一种进行性疾病。其特征是心动过速、导致频繁昏厥和自主性呕吐“危象”的直立性低血压、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。这种疾病不仅破坏了自主神经系统的功能，而且还以疼痛和温度感觉的严重缺陷为特征，并具有CNS表现。FD是由于基因IKBKAP在剪接受体位点（IVS 20 + 6 T>C; 99.5%的患者）中的突变导致截短mRNA的转录，该截短mRNA靶向无义介导的衰变。编码的蛋白IKAP的功能尚未解决。很明显，在Ikbkap基因完全缺失的小鼠死亡中， 由于神经形成和血管发生失败，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，我们制作了2种条件性敲除小鼠模型，其中Ikbkap从神经嵴（使用Wnt 1-cre）或中枢神经系统（CNS）的神经元中缺失，但不是外周神经系统（PNS;使用Ta 1微管蛋白-cre）。Wnt 1-cre/Ikbkap小鼠在出生后24小时内死亡，对其PNS的分析表明人类疾病的重演，交感神经、副交感神经和TrkA+疼痛和温度感应神经元显著减少，因此提供了用于确定疾病中发育中断的极好模型。我们发现PNS神经元在发育过程中的减少是由于祖细胞和有丝分裂后神经元的凋亡。Ta 1微管蛋白-cre/Ikbkap也忠实地概括了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个月时死亡，它们的病情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FD的渐进性退化机制。这些结果不仅表明在神经系统中Ikbkap的缺失足以引起FD，而且我们有两个独立的模型，其中我们可以在成人的发育与进展期间剖析CNS和PNS中IKAP的功能。由于自主神经系统（ANS）是一个电路，包括CNS和PNS组件，我们建议在这里采取系统范围的方法来确定IKAP在CNS和PNS的功能。随着对需要IKAP的关键通路的理解，长期目标是开发策略以防止FD和其他HSAN中CNS和PNS神经元的进行性变性。