PATHOBIOLOGY OF AMP DEAMINASE DEFICIENCY

描述：AMP脱氨酶（AMPD）缺乏可以说是最常见的 在高加索人和非洲裔美国人中遗传缺陷。 一 AMPD 1基因中的一个突变等位基因会导致 骨骼肌细胞中的这种酶活性， 突变等位基因易患代谢性肌病。 对于这种突变等位基因的杂合子个体， 如果他们患上充血性心脏病等疾病， 失败，大概是因为心肌细胞中AMPD活性降低。 本提案有四个主要目标：1确定AMPD是否 缺陷本身是造成观察到的存活期延长的原因 在心力衰竭和机制（S），通过减少活动， 酶影响心脏功能。 2. AMPD小鼠模型的建立 通过靶向破坏AMPD 1基因来评估 这种酶活性降低的分子和生理后果 在骨骼肌和心肌中。 3. 继续以前开始的研究， 确定AMPD 1肽中的功能结构域以及这些功能结构域的作用 结构域在控制这种酶的活性中起作用。 4. 继续进行 这些研究已经确定了一种新的机制， 由于AMPD 1初级转录本的潜在重要性， 选择性剪接来控制这种酶的活性， 这种常见遗传疾病的表型表现。

DESCRIPTION: Deficiency of AMP deaminase (AMPD) is arguably the most common inherited defect in the Caucasian and African-American populations. A single mutant allele in the AMPD1 gene leads to a high grade deficiency of this enzyme activity in skeletal myocytes, and patients who inherit two mutant alleles have are predisposed to develop a metabolic myopathy. Individuals who are heterozygous for this mutant allele have a striking survival advantage if they develop a disorder such as congestive heart failure, presumably because of reduced AMPD activity in cardiac myocytes. There are four major objectives of this proposal: 1 Determine if AMPD deficiency per se is responsible for the prolongation of survival observed in heart failure and the mechanism(s) by which reduced activity of this enzyme affects cardiac function. 2. Develop a murine model of AMPD deficiency through targeted disruption of the AMPD 1 gene to assess the molecular and physiological consequences of reduced activity of this enzyme in skeletal and cardiac muscle. 3. Continue studies begun previously to identify functional domains in the AMPD1 peptide and what roles these domains play in controlling the activity of this enzyme. 4. Pursue ongoing studies which have defined a novel mechanism for regulation of alternative splicing of the AMPD1 primary transcript because of the potential importance of alternative splicing for the control of this enzyme activity and the phenotypic manifestations of this common inherited disorder.