Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I.
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.
Summar
Marshall L
ML
Division of Medical Genetics, Department of Pediatrics and Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA. marshall.summar@vanderbilt.edu
Hall
Lynn
L
Christman
Brian
B
Barr
Frederick
F
Smith
Heidi
H
Kallianpur
Asha
A
Brown
Nancy
N
Yadav
Meeta
M
Willis
Alecia
A
Eeds
Angela
A
Cermak
Emma
E
Summar
Samantha
S
Wilson
Ann
A
Arvin
Molly
M
Putnam
Allison
A
Wills
Melissa
M
Cunningham
Gary
G
D016026:Bone Marrow Transplantation; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000172:deficiency / Q000235:genetics*; D020165:Carbamoyl-Phosphate Synthase I Deficiency Disease / Q000235:genetics; D016009:Chi-Square Distribution; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis; D007231:Infant, Newborn; D008954:Models, Biological; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism
D009569:Nitric Oxide; D002222:Carbamoyl-Phosphate Synthase (Ammonia)