Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I
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:
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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
References (22)
- et al.
Carbamoyl phosphate synthetase I of human liver. Purification, some properties and immunological cross-reactivity with the rat liver enzyme
Biochim. Biophys. Acta
(1981) - et al.
Endogenous nitric oxide and pulmonary vascular tone in the neonate
J. Pediatr. Surg.
(1996) - et al.
Effect of inhaled nitric oxide on endothelin-1 and cyclic guanosine 5′-monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension
J. Pediatr.
(1997) - et al.
Therapeutic implications of human endothelial nitric oxide synthase gene polymorphism
Trends Pharmacol. Sci.
(2001) - et al.
Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery
J. Pediatr.
(2003) - et al.
Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene
Gene
(2003) - et al.
Mammalian urea cycle enzymes
Annu. Rev. Genet.
(1986) - et al.
Physical location of the site for N-acetyl-l-glutamate, the allosteric activator of carbamoyl phosphate synthetase, in the 20-kilodalton COOH-terminal domain
Biochemistry
(1989) - et al.
A structure-reactivity study of the binding of acetylglutamate to carbamoyl phosphate synthetase I
Eur. J. Biochem.
(1990) - et al.
The effect of inhaled nitric oxide on the pulmonary circulation of the neonatal pig
Pediatr. Res.
(1994)
Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries
Am. J. Physiol.
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CPS1: Looking at an ancient enzyme in a modern light
2020, Molecular Genetics and MetabolismCitation Excerpt :The SNP rs1047891 encodes a C > A transversion, a missense mutation in exon 36 leading to the incorporation of asparagine instead of threonine at amino acid residue 1405 (T1405N). T1405N was initially associated with protection against neonatal hypertension [99], as well as post-cardiac surgery and post-bone marrow transplant complications [100]. However, T1405N has subsequently been shown to functionally impair CPS1 activity by 30–40% [101], contradicting the hypothesis that T1405N promotes increased circulating arginine and endothelial nitric oxide signaling (eNOS) [100].
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2016, Psychiatry ResearchWhole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis
2016, American Journal of Human GeneticsCitation Excerpt :Moreover, according to the GTEx Portal database, there is no evidence of an expression quantitative trait loci (eQTL) effect for rs1047891. Nonetheless, the CPS1 p.Thr1412Asn missense substitution is located within a region critical for N-acetyl-glutamate binding and has been reported to result in 20%–30% higher enzymatic activity19 and to influence vascular function.15 We initially assessed the association of rs150813342 with GFI1B expression by using Affymetrix GeneChip Human Exon 1.0 ST Array data on whole-blood RNA available from 881 Framingham Heart Study participants.20
Fatal hyperammonemia and carbamoyl phosphate synthetase 1 (CPS1) deficiency following high-dose chemotherapy and autologous hematopoietic stem cell transplantation
2015, Molecular Genetics and MetabolismCitation Excerpt :In conclusion, several PTM of CPS1 may have contributed to the clinical course in the patient but this is likely not the main factor. Finally, several gene polymorphisms in the CPS1 gene were described to increase the risk for developing hyperammonemia in the course of chemotherapy and bone marrow transplantation [48,49]. One specific CPS1 gene polymorphism (exon 36: c.4217C > A, p.T1406N) has been clinically correlated with an increased risk of bone marrow transplantation-associated complications [48,49] and complications in other conditions [50,51].