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

描述(申请人提供)：通过过去20年的合作工作，我们发现TRPV4基因突变会导致两种等位基因神经肌肉疾病，肩周型脊髓性肌萎缩症(SPSMA)和2C型夏科-玛丽-图思病(CMT2C，也称为遗传性运动和感觉神经病IIC(HMSN IIC))。SPSMA和CMT2C均以外周轴索神经病为特征。这些等位基因紊乱背后的轴突变性的发病机制尚不清楚。TRPV4基因编码一个瞬时受体电位(Trp)阳离子通道V亚家族成员4(TRPV4)，是一种已知的钙离子通透性非选择性阳离子通道。我们的初步研究表明，SPSMA和CMT2C连接的突变型TRPV4通道显著增加了对钙的开放几率，导致当这些通道在转染的肿瘤细胞系中表达时，细胞内钙浓度增加。这些数据表明，细胞内钙浓度的异常变化在轴突变性中具有潜在的致病作用。到目前为止，在24个不相关的家系和患有不同形式轴索神经病的孤立病例中发现了11种不同的突变。由于TRPV4连锁轴索神经病代表了一组新发现的神经肌肉疾病(TRPV4-通道病)，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。在这一应用中，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的问题，包括(1)TRPV4连锁轴突神经病的遗传学、临床变异和潜在的基因-表型相关性的总体概况；(Ii)运动神经元中突变的TRPV4通道的特性，这是该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以及致病机制的分子基础提供急需的信息，从而为合理的治疗提供病理生理学基础。当考虑到TRPV4的钙通道活性可以被一些已知的激动剂和拮抗剂调节时，这一点可能尤其正确。由于TRPV4可以被广泛的物理和化学刺激激活，而且钙内流增加与许多其他神经退行性疾病有关，因此该项目的结果可能对其他神经退行性疾病的研究也有重要意义。

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.