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

描述（由申请人提供）：通过过去20年的合作工作，我们发现TRPV 4基因突变导致两种等位基因神经肌肉疾病，即肩胛腓骨脊髓性肌萎缩症（SPSMA）和Charcot-Marie-Tooth病2C型（CMT 2C，也称为遗传性运动和感觉神经病IIC型（HMSN IIC））。SPSMA和CMT 2C均以外周轴索神经病变为特征。这些等位基因疾病背后的轴突变性的发病机制尚不清楚。TRPV 4基因编码瞬时受体电位（TRP）阳离子通道，亚家族V，成员4（TRPV 4），一种已知的Ca 2+渗透性非选择性阳离子通道。 我们的初步研究表明，SPSMA和CMT 2C连接的突变体TRPV 4通道有显着增加的开放概率Ca 2+，导致细胞内Ca 2+浓度增加时，这些通道在转染的肿瘤细胞系中表达。 这些数据表明，在轴突变性细胞内Ca 2+浓度的异常变化的潜在致病作用。迄今为止，在24个不相关的家族和孤立病例中发现了11种不同的突变，这些突变具有不同形式的轴突神经病。 由于TRPV 4-连锁轴突神经病代表了一组新发现的神经肌肉疾病（TRPV 4-channelopathies），许多关于其遗传和临床特征以及致病机制的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，以解决一些关键的未解决的问题，包括（1）TRPV 4连锁轴突神经病的遗传学，临床变异和潜在的基因型-表型相关性的整体图片-（II）运动神经元中突变TRPV 4通道的特性，这组疾病中主要受影响的细胞类型。 该项目的成功完成不仅将为了解这些疾病的性质提供急需的信息，而且还将为致病机制的分子基础提供信息，从而为合理的治疗提供病理生理学基础。当考虑到TRPV 4的钙通道活性可以由一些已知的激动剂和拮抗剂调节时，这可能尤其正确。由于TRPV 4可以被广泛的物理和化学刺激激活，并且增加的Ca 2+内流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。

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.