PATHOBIOLOGY OF AMP DEAMINASE DEFICIENCY

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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.