Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I

https://doi.org/10.1016/j.ymgme.2003.11.014Get rights and content

Abstract

Carbamyl phosphate synthetase I (CPSI) determines the rate-limiting entry of free ammonia into the urea cycle. Disruption of CPSI affects the liver’s ability to remove waste nitrogen and produce arginine, citrulline, and urea. Arginine is the necessary precursor for the critical biomolecule, nitric oxide (NO). We have studied the classic model of CPSI deficiency, which results in severe hyperammonemia, and identified a large number of molecular defects. A number of CPSI polymorphisms have been found that appear to result in functional consequences. We have examined the association of these polymorphisms with various environmental stress conditions and found that certain CPSI alleles are associated with clinical outcome. We refer to these associations as environmentally determined genetic expression (EDGE) affects. In addition to studies of classic CPSI deficiency, we have developed data for the EDGE concept in post-cardiac surgery-related pulmonary hypertension, hepatic veno-occlusive disease after bone marrow transplantation, and persistent pulmonary hypertension of the newborn. We have linked these outcomes and genotypes to the availability of the urea cycle intermediates, citrulline and arginine, and their role in NO synthesis. We hypothesize that these polymorphisms affect the functional efficiency of CPSI and thus the entire urea cycle and as such, the availability of the NO substrates. By piecing together the various functional aspects of the urea cycle changes we have seen, we can better understand the clinical vulnerabilities of patients in environmentally stressful situations. This knowledge should allow us to design intervention strategies to either predict or modify the associated adverse outcomes.

Section snippets

Environmentally determined genetic expression

With the completion of the human genome project and the rapid accumulation of new information about common variations in the genetic code, the study of the interactions between genetic differences and the environment becomes possible. We have developed the concept of environmentally determined genetic expression (EDGE) studies to provide a framework for the consideration of both elements, statistically and functionally. EDGE can best be summed up as follows:

  • 1.

    genetically encoded differences in

Neonatal and late-onset CPSI deficiency

Through our work on CPSI deficiency (CPSID), including mutation analysis and prenatal linkage studies, we have collected DNA from families with at least one child affected with CPSID. The diagnosis of CPSID in these patients is based on liver enzyme analysis. Patients with less than 10% of normal CPSI activity and a clinical history of hyperammonemia are considered to have CPSID. Mutation screening was performed by single strand conformation polymorphism analysis. Sequencing was performed on

Results

The results are presented in the order of their relative genetic or environmental effect. The classic form of CPSID had the least environmental effect on the phenotype. This is followed by the later onset forms of CPSID. While the phenotypes vary for the rest of the disorders, we subjectively ranked BMT as the most severe environmental situation followed by post-cardiac surgery and then pulmonary hypertension of the newborn. We found correlations in all our groups between the development of

Discussion

We have presented an eclectic group of data from a number of clinical situations, and are using these examples to illustrate the interaction between genetics and the environment. With the completion of the human genome sequencing project, these types of studies are the next step in examining the relevance of genetic variation in common conditions. Our EDGE model is an effort to move beyond basic association studies and relate quantitative and qualitative changes to observed pathophysiology. In

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