The molecular study of defects in ammonia metabolism has been generally limited to rare inborn errors of metabolism. Hyperammonemia, however, is much more common and is associated with non-genetic conditions and environmental exposures. These conditions usually involve some degree of physical hepatic damage or disruption. A common example is the frequent hyperammonemia observed in patients following administration of the drug valproic acid. With the increase in bone marrow transplant procedures (BMT), a number of hyperammonemic deaths have been reported. In addition, more subtle toxicities may result from mild increases in urea cycle precursors (glutamine, alanine, glycine, etc.), or decreases in urea cycle intermediates (arginine and citrulline). Whatever the triggering event, disturbances in ammonia clearance reflect physical or biochemical effects on the urea cycle. My research has focused on characterizing the gene encoding the first, rate-limiting step of ureagenesis, carbamyl phosphate synthetase I (CPSI). In patient studies, I have found a number of rare CPSI molecular defects resulting in severe inherited disruptions of the urea cycle. During these studies, I have also identified a common exonic polymorphism which may qualitatively affect CPSI function. This study is designed to examine the clinical and biochemical significance of this polymorphism and identify other potentially relevant changes in the CPSI gene. These changes may play a key role in the susceptibility to urea cycle toxicity secondary to drug or toxin exposure. I will study the functional affects of this change on expressed CPSI protein using site-directed mutants of our CPSI expression clone. In addition to studying the functional characteristics of this polymorphism, I will determine if there is any association between the CPSI genotype and the toxicity observed in patients undergoing BMT. As part of my collaboration with Dr. Brian Christman, we have observed significant changes in urea cycle intermediates following induction chemotherapy for BMT, and have preliminary data showing disequilibrium with the CPSI polymorphism. We will further test the correlation between the CPSI polymorphic genotypes with the presence of observed biochemical/clinical toxicity in patients beginning therapy with valproic acid. We will also screen the CPSI gene for other exonic polymorphisms which can be tested. We will establish the role of these common polymorphisms in the urea-cycle related toxicity seen in these patients. Positive results in this study will lead to further study of other conditions involving the derangement of waste nitrogen disposal.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-JPM-B (01))
Program Officer
Packenham, Joan P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Schools of Medicine
United States
Zip Code
Häberle, Johannes; Shchelochkov, Oleg A; Wang, Jing et al. (2011) Molecular defects in human carbamoy phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations. Hum Mutat 32:579-89
Vadivel, Arul; Aschner, Judy L; Rey-Parra, Gloria J et al. (2010) L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats. Pediatr Res 68:519-25
Kallianpur, A R; Hall, L D; Yadav, M et al. (2005) The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 35:1155-64
Moore, Jason H; Boczko, Erik M; Summar, Marshall L (2005) Connecting the dots between genes, biochemistry, and disease susceptibility: systems biology modeling in human genetics. Mol Genet Metab 84:104-11
Kallianpur, Asha R; Hall, Lynn D; Yadav, Meeta et al. (2004) Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer. Cancer Epidemiol Biomarkers Prev 13:205-12
Barr, Frederick E; Beverley, Heidi; VanHook, Kristin et al. (2003) Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery. J Pediatr 142:26-30
Summar, M L; Hall, L D; Eeds, A M et al. (2003) Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene. Gene 311:51-7
Pearson, D L; Dawling, S; Walsh, W F et al. (2001) Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med 344:1832-8