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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK012413-31
Application #
2015945
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mckeon, Catherine T
Project Start
1991-09-30
Project End
1997-06-30
Budget Start
1997-05-01
Budget End
1997-06-30
Support Year
31
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Loh, E; Rebbeck, T R; Mahoney, P D et al. (1999) Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure. Circulation 99:1422-5
Hisatome, I; Morisaki, T; Kamma, H et al. (1998) Control of AMP deaminase 1 binding to myosin heavy chain. Am J Physiol 275:C870-81
Morisaki, H; Morisaki, T; Newby, L K et al. (1993) Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect. J Clin Invest 91:2275-80
Morisaki, T; Holmes, E W (1993) Functionally distinct elements are required for expression of the AMPD1 gene in myocytes. Mol Cell Biol 13:5854-60
Sabina, R L; Fishbein, W N; Pezeshkpour, G et al. (1992) Molecular analysis of the myoadenylate deaminase deficiencies. Neurology 42:170-9
Morisaki, T; Gross, M; Morisaki, H et al. (1992) Molecular basis of AMP deaminase deficiency in skeletal muscle. Proc Natl Acad Sci U S A 89:6457-61
Mineo, I; Holmes, E W (1991) Exon recognition and nucleocytoplasmic partitioning determine AMPD1 alternative transcript production. Mol Cell Biol 11:5356-63
Mineo, I; Clarke, P R; Sabina, R L et al. (1990) A novel pathway for alternative splicing: identification of an RNA intermediate that generates an alternative 5' splice donor site not present in the primary transcript of AMPD1. Mol Cell Biol 10:5271-8
Moseley, W S; Morisaki, T; Sabina, R L et al. (1990) Ampd-2 maps to distal mouse chromosome 3 in linkage with Ampd-1. Genomics 6:572-4
Morisaki, T; Sabina, R L; Holmes, E W (1990) Adenylate deaminase. A multigene family in humans and rats. J Biol Chem 265:11482-6

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