Molecular basis of Scapuloperoneal SMA and Charcot-Marie-Tooth disease type 2C

肩胛腓骨 SMA 和 2C 型腓骨肌萎缩症的分子基础

• 批准号: 8440280
• 负责人: Han-Xiang Deng
• 金额: $ 33.8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440280
• 关键词: Address; Affect; Agonist; Amyotrophic Lateral Sclerosis; Axon; Axonal Neuropathy; Biochemical; Biological Assay; Biotinylation; Calcium; Calcium Channel; Cations; Cell Survival; Cell surface; Cells; Charcot-Marie-Tooth Disease; Chemicals; Clinical; Clinical Medicine; Confocal Microscopy; Data; Development; Disease; Disease Outcome; Family; Genes; Genetic; Genotype; Goals; Hereditary Motor and Sensory Neuropathies; Image; In Vitro; Link; Molecular; Motor Neuron Disease; Motor Neurons; Muscular Atrophy; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuromuscular Diseases; Neuropathy; Pathogenesis; Pathology; Peripheral; Phenotype; Prevalence; Probability; Property; Role; Spastic Paraplegia; Spinal; Spinal Muscular Atrophy; Stimulus; Transgenic Mice; Tumor Cell Line; Variant; Work; axonal degeneration; base; cell type; design; effective therapy; in vivo; insight; member; mouse model; mutant; nervous system disorder; neurophysiology; novel; patch clamp; receptor

DESCRIPTION (provided by applicant): Through collaborative work over the past 20 years, we have discovered that mutations in the TRPV4 gene cause two allelic neuromuscular disorders, scapuloperoneal spinal muscular atrophy (SPSMA) and Charcot- Marie-Tooth disease type 2C (CMT2C, also known as hereditary motor and sensory neuropathy type IIC (HMSN IIC)). Both SPSMA and CMT2C are characterized by peripheral axonal neuropathy. The pathogenesis of the axonal degeneration underlying these allelic disorders is not known. The TRPV4 gene encodes a transient receptor potential (TRP) cation channel, subfamily V, member 4 (TRPV4), a known Ca2+-permeable, non-selective cation channel. Our preliminary studies indicate that the SPSMA- and CMT2C-linked mutant TRPV4 channels have remarkably increased open probability to Ca2+, leading to an increased intracellular Ca2+ concentration when these channels are expressed in transfected tumor cell lines. These data suggest a potentially pathogenic role for abnormal changes in intracellular Ca2+ concentration in axonal degeneration. To date, 11 different mutations have been found in 24 unrelated families and isolated cases with variant forms of axonal neuropathies. Because the TRPV4-linked axonal neuropathies represent a newly identified group of neuromuscular disorders (TRPV4-channelopathies), many essential questions about their genetic and clinical features, and pathogenic mechanism remain to be addressed. In this application, we propose two closed related specific aims to address a few of the key unresolved issues, including (1) the overall picture of the genetics, clinical variants and potential genotype-phenotype correlation of the TRPV4-linked axonal neuropathies~ (II) the properties of mutant TRPV4 channels in motor neurons, the predominantly affected cell type in this group of disease. Successful completion of this project will provide much needed information for understanding not only the nature of these diseases, but also the molecular basis of the pathogenic mechanism, and therefore to provide a pathophysiological basis for rational therapies. This may be especially true when considering that the calcium channel activity of TRPV4 can be regulated by some known agonists and antagonists. Because TRPV4 can be activated by a wide range of physical and chemical stimuli, and increased Ca2+ influx has been associated with a number of other neurodegenerative diseases, the outcome of this project may also have important implications in the studies of other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: We have recently discovered that mutations in TRPV4 cause scapuloperoneal spinal muscular atrophy (SPSMA) and Charcot-Marie-Tooth disease type 2C (CMT2C, also known as hereditary motor and sensory neuropathy type IIC (HMSN IIC)). This project is designed to understand the genetic and clinical features as well as the molecular mechanism of TRPV4-linked axonal neuropathies. Understanding the molecular mechanism of TRPV4-linked axonal degeneration may provide a pathophysiological basis for design of rational therapies for SPSMA and CMT2C, with possible implications in other neurological diseases.

描述（申请人提供）：通过过去20年的合作工作，我们发现TRPV4基因的突变会导致两种等位基因神经肌肉疾病，即肩胛腓脊髓肌萎缩症（SPSMA）和2C型腓骨肌萎缩症（CMT2C，也称为IIC型遗传性运动和感觉神经病（HMSN IIC））。 SPSMA 和 CMT2C 均以周围轴突神经病变为特征。这些等位基因疾病的轴突变性的发病机制尚不清楚。 TRPV4 基因编码瞬时受体电位 (TRP) 阳离子通道，亚家族 V，成员 4 (TRPV4)，一种已知的 Ca2+ 渗透性、非选择性阳离子通道。 我们的初步研究表明，SPSMA 和 CMT2C 连接的突变体 TRPV4 通道显着增加了 Ca2+ 的开放概率，当这些通道在转染的肿瘤细胞系中表达时，导致细胞内 Ca2+ 浓度增加。 这些数据表明细胞内 Ca2+ 浓度的异常变化在轴突变性中具有潜在的致病作用。迄今为止，已在 24 个不相关的家族和患有不同形式轴突神经病的孤立病例中发现了 11 种不同的突变。 由于 TRPV4 相关轴突神经病代表了一组新发现的神经肌肉疾病（TRPV4 通道病），因此有关其遗传和临床特征以及致病机制的许多基本问题仍有待解决。 在本申请中，我们提出了两个密切相关的具体目标来解决一些关键的未解决问题，包括（1）TRPV4相关轴突神经病的遗传学、临床变异和潜在基因型-表型相关性的总体情况〜（II）运动神经元中突变TRPV4通道的特性，运动神经元是这组疾病中主要受影响的细胞类型。 该项目的成功完成将为了解这些疾病的本质和致病机制的分子基础提供急需的信息，从而为合理治疗提供病理生理学基础。当考虑到 TRPV4 的钙通道活性可以通过一些已知的激动剂和拮抗剂调节时，这可能尤其正确。由于TRPV4可以被广泛的物理和化学刺激激活，并且Ca2+流入增加与许多其他神经退行性疾病相关，因此该项目的结果也可能对其他神经退行性疾病的研究具有重要意义。 公共健康相关性：我们最近发现 TRPV4 突变会导致肩胛腓骨脊髓性肌萎缩症 (SPSMA) 和 2C 型夏科-马里-图思病 (CMT2C，也称为 IIC 型遗传性运动和感觉神经病 (HMSN IIC))。该项目旨在了解 TRPV4 相关轴突神经病的遗传和临床特征以及分子机制。 了解 TRPV4 相关轴突变性的分子机制可能为 SPSMA 和 CMT2C 的合理疗法的设计提供病理生理学基础，并可能对其他神经系统疾病产生影响。