WHY DO MUTATIONS IN IKBKAP CAUSE FAMILIAL DYSAUTONOMIA?

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，家族性自主神经异常（FD，也称为Riley Day综合征）。这种疾病是一种发展性和进行性疾病。其特点是心动过速、体位性低血压（导致频繁晕厥和自主呕吐“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陷为特征，并有中枢神经系统表现。FD是由于IKBKAP基因在剪接受体位点（IVS20+6T>C； 99.5%的患者）发生突变，导致截断mRNA的转录，以无义介导的衰变为目标。编码蛋白IKAP的功能尚不清楚。它显然在ikkap基因完全缺失的小鼠死亡中起着至关重要的作用

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.