PATHOBIOLOGY OF AMP DEAMINASE DEFICIENCY

描述：AMP脱氨酶缺乏症(AMPD)是最常见的 高加索人和非裔美国人的遗传缺陷。一个 AMPD1基因的单个突变等位基因导致高度缺乏 这种酶在骨骼肌细胞中的活性，以及遗传了两个 突变的等位基因容易患上代谢性肌病。 这种突变等位基因杂合子的个体具有惊人的 如果他们患有充血性心脏病等疾病，他们的生存优势 失败，可能是因为心肌细胞中AMPD活性降低。 这项提议有四个主要目标：1确定AMPD是否 缺乏本身就是观察到的生存时间延长的原因。 在心力衰竭中的作用及其机制(S) 酶会影响心脏功能。2.建立AMPD小鼠模型 通过靶向破坏AMPD 1基因来评估 该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，以 确定AMPD1多肽中的功能结构域，以及这些结构域在其中的作用 结构域在控制这种酶的活性方面起着作用。4.持续追求 定义了一种新的替代性监管机制的研究 由于潜在的重要性，AMPD1初级转录本的剪接 选择性剪接来控制这种酶的活性和 这种常见遗传性疾病的表型表现。

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.