A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies
A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies
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DOI：
10.1093/hmg/ddl068
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发表时间：
2006-05-01
影响因子：
3.5
通讯作者：
Agnew, WS
中科院分区：
文献类型：
--
作者：
Zhong, XL;Liu, JRR;Agnew, WS
高度选择性的剪接基因可能为疾病突变提供复杂的靶点。错义突变引起的结构变化可能会不同地影响替代基因产物的活性，而错义突变、沉默突变和非编码突变可能会改变剪接变体表达的发育调节。CACNA1H是一个编码Ca(V)3.2低电压激活的T型钙通道的人类基因，与神经元的爆发性行为有关，并与30多个突变有关，这些突变显然容易导致儿童失神癫痫(CAE)和其他特发性全身性癫痫(IGES)。生物物理性质，包括错义突变的影响，以前已经对转化细胞系中表达的单一剪接形式的Ca(V)3.2进行了评估。我们在这里证明了CACNA1H在12-14个位点上交替剪接，能够产生功能转录本和非功能转录本。不同的细胞质和胞外蛋白结构域表明，门控行为、对神经调节的敏感性以及与细胞外基质的相互作用可能存在差异。选定的生理性Ca(V)3.2形态的生物物理特征揭示了动力学和稳态门控参数的变化，最有可能影响膜的激发。这些变化与之前研究的突变报告的变化相当或更大。错义CAE和IGE突变聚集在与异常剪接相关的片段附近。错义和沉默突变被发现破坏、创建或改变预测的外显子剪接增强子序列的调控特异性，这些外显子剪接增强序列可能控制剪接调控。我们讨论了CA(V)3.2亚基CACNA1H表达的范例，这可能会影响未来的基础和临床研究。
Highly alternatively spliced genes may provide complex targets for disease mutations. Structural changes created by missense mutations may differentially affect the activity of alternative gene products, whereas missense, silent and non-coding mutations may alter developmental regulation of splice variant expression. CACNA1H is a human gene encoding Ca(v)3.2 low-voltage-activated, T-type calcium channels associated with bursting behavior in neurons and has been linked to more than 30 mutations apparently predisposing to childhood absence epilepsy (CAE) and other idiopathic generalized epilepsies (IGEs). Biophysical properties, including the effects of missense mutations, have been evaluated previously for a single splice form of Ca(v)3.2 expressed in transformed cell lines. We here show that CACNA1H is alternatively spliced at 12-14 sites, capable of generating both functional and non-functional transcripts. Variable cytoplasmic and extracellular protein domains point to likely differences in gating behavior, sensitivity to neuromodulation and interactions with extracellular matrix. Biophysical profiles of selected physiological Ca(v)3.2 forms reveal variations in kinetics and steady-state gating parameters, most likely to affect membrane firing. These were comparable to or larger than changes reported for previously studied mutations. Missense CAE and IGE mutations were clustered near segments associated with anomalous splicing. Missense and silent mutations were found to destroy, create or change the regulatory specificity of predicted exonic splicing enhancer sequences that may control splicing regulation. We discuss a paradigm for CACNA1H expression of Ca(v)3.2 subunits, which may influence future basic and clinical studies.