GENETIC AND MOLECULAR ANALYSIS OF LONG QT SYNDROME

长 QT 综合征的遗传和分子分析

• 批准号: 2210559
• 负责人: CAROL A SATLER
• 金额: $ 8.1万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2210559
• 关键词: artificial chromosomes; clone cells; computer assisted sequence analysis; genetic disorder; genetic disorder diagnosis; genetic library; genetic markers; genetic polymorphism; heart conduction system; heart disorder; heart disorder diagnosis; human subject; linkage mapping; molecular cloning; molecular pathology; nucleic acid sequence; potassium channel; restriction fragment length polymorphism; syndrome

The objective of the proposed research is to isolate, characterize, and understand the human genes involved in heritable cardiac conduction disease. Identification of these genes will enhance our understanding of the molecular mechanisms of cardiac conduction and may play a significant role in the development of new diagnostic and therapeutic modalities for cardiac arrhythmias. Specifically, this proposal will focus on the clinically heterogeneous inherited cardiac conduction disorder, long QT syndrome (LQT). Affected individuals have an pathognomic electrocardiographic abnormalities such as an abnormal prolongation of the QT interval with asymmetric or noted T or U waves. We have characterized two large multi-generational families with this syndrome which predisposes affected members to seizures, recurrent fainting, and sudden death at an early age from ventricular tachyarrhythmias. We are currently identifying other families with LQT. The goal of this research proposal is to isolate and characterize the gene locus (loci) responsible for LQT. To date, our understanding of the molecular and cellular phenotype of LQT is limited, though it is believed to be a molecular defect in cardiac muscle cell excitability. Recently, genetic linkage analysis has been performed in a family with LQT(1). A DNA marker at the Harvey ras-1 locus (H-ras-1) has been linked to LQT in this family. This finding confirms the genetic basis of this trait and localizes the responsible gene to the vicinity of the H-ras-1 gene on the short arm of chromosome 11. Physiological data demonstrates that the product of the H-ras-1 gene, p21 ras protein, regulates cardiac potassium channels(2). Thus, based on its physiologic role in modulating cardiac ion transport, that ras is a reasonable candidate for the abnormal gene responsible for LQT. However, it is important to note that even though linkage has been established for this family to H-ras-1 locus, it has not been demonstrated that H-ras-1 is the disease gene. Through the identification and characterization of new families with LQT, the establishment of genomic DNA bank derived from lymphoblastoid cell lines of family members, and genetic linkage analysis studies with H-ras-1 markers and other newly developed DNA markers, we will demonstrate if these families are linked to H-ras-1 gene locus. Based on these results, further studies using SSCP analysis, yeast artificial chromosome libraries and CA polymorphisms will be designed to either evaluate ras, the region near ras or another newly defined locus. The purpose of this research proposal is to determine whether H-ras-1 gene is responsible for LQT in these families. If the H-ras-1 gene is not responsible, then we will identify the responsible gene. Our ultimate aim is to structurally and functionally characterize the gene so that we can better understand the molecular mechanism of disease.

拟议研究的目的是隔离，表征和 了解与遗传性心脏传导有关的人类基因 疾病。 这些基因的识别将增强我们对 心脏传导的分子机制，可能发挥重要作用 在开发新的诊断和治疗方式中的作用 心律不齐。 具体来说，该建议将重点放在 临床上异质的遗传性心脏传导障碍，长QT 综合征（LQT）。 受影响的人有病理 心电图异常，例如异常延长 QT间隔不对称或不对称的T或U波。 我们已经表征了 这个综合征的两个大型多代家族 影响成员癫痫发作，反复发作和突然死亡 心室心律失常的幼年。 我们目前正在确定 LQT的其他家庭。 该研究建议的目的是隔离 并表征负责LQT的基因基因座（基因座）。 迄今为止，我们的 对LQT的分子和细胞表型的了解有限， 虽然被认为是心肌细胞中的分子缺陷 兴奋性。 最近，在一个家庭中进行了遗传连锁分析 LQT（1）。 Harvey Ras-1基因座（H-RAS-1）的DNA标记已连接 到这个家庭的LQT。 这一发现证实了这一点的遗传基础 特质并将负责的基因定位到H-RAS-1附近 染色体11的短臂上的基因。生理数据证明 H-Ras-1基因P21 RAS蛋白的产物调节心脏 钾通道（2）。 因此，基于其在调节中的生理作用 心脏离子运输，RAS是异常的合理候选者 负责LQT的基因。 但是，重要的是要注意 尽管已经为这个家庭建立了与H-RAS-1基因座建立的联系，但 尚未证明H-RAS-1是疾病基因。 通过 具有LQT的新家庭的识别和表征 建立源自淋巴母细胞系的基因组DNA库 家庭成员以及使用H-RAS-1标记的遗传连锁分析研究 和其他新开发的DNA标记，我们将证明是否 家庭与H-RAS-1基因基因座有关。 基于这些结果，进一步 使用SSCP分析，酵母人工染色体文库和CA的研究 多态性将设计为评估RA，RAS，RAS附近的区域 或另一个新定义的基因座。 该研究建议的目的是 确定H-RAS-1基因是否负责这些家族的LQT。 如果H-RAS-1基因不负责，那么我们将确定 负责的基因。 我们的最终目标是在结构和功能上 表征该基因，以便我们可以更好地理解分子 疾病机理。