Overlapping cistrons in a family of ion channel genes

 描述(申请人提供)：我们发现编码P/Q型电压门控钙通道(VGCC)的CACNA1A基因是双顺反子。CACNA1AmRNA编码A1a亚基和第二个蛋白质a1ACT，a1ACT是一种转录因子，由于一个隐蔽的内部核糖体进入位点(IRES)，该蛋白质被翻译为第二个开放阅读框架。在同一细胞中同时表达两种蛋白质，其中一种是转录因子，这可能是钙通道和其他细胞基因协调一系列基因表达的一种强有力的策略。为了理解这类新的IRES和双顺反子基因，我们将：1.确定CACNA1AIRES是如何受RNA结合蛋白和miRNAs调控的；2.定义VGCC家族双顺反子基因的新特性。3.确定双顺反子基因表达改变是否导致VGCC疾病的复杂表型。这项研究将有助于我们了解双顺反子细胞基因的生物学，特别是在其他VGCC中，IRES调控机制和编码的蛋白质的性质，以及在复杂人类遗传病的发病和治疗中可能发挥的作用。

 DESCRIPTION (provided by applicant): We have discovered that the CACNA1A gene, which encodes the P/Q type voltage gated calcium channel (VGCC) is bicistronic. The CACNA1A mRNA encodes both the a1A subunit and a second protein, a1ACT, a transcription factor, that is translated as a second open reading frame due to a cryptic internal ribosomal entry site (IRES). Simultaneous expression of two proteins in the same cellular mRNA, one of which is a transcription factor, may be a powerful strategy used by calcium channels and other cellular genes to coordinate expression of an ensemble of genes. To understand this new class of IRES and bicistronic genes we will: 1. Determine how the CACNA1A IRES is regulated by RNA-binding proteins and miRNAs; 2. Define the novel properties of bicistronic genes of the VGCC family. 3. Determine whether altered bicistronic gene expression leads to the complex phenotypes of VGCC disorders. This study will help us to understand the biology of bicistronic cellular genes in particular among other VGCCs, the nature of the IRES regulatory mechanisms and proteins they encode, and the possible role in the pathogenesis and treatment of complex human genetic disease.