Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene

Summar, Marshall; Hall, Lynn; Eeds, Angela; Hutcheson, Holli; Kuo, Alan; Willis, Alecia; Rubio, Vicente; Arvin, Molly; Schofield, J. Paul; Dawson, Elliott P.

doi:10.1016/s0378-1119(03)00528-6

Cited by 52 publications

(55 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Expected values for HFE alleles were calculated using allele frequencies determined previously in (1) a sample of adults from Tennessee who attended Vanderbilt-affiliated internal medicine clinics and whose racial/ethnic background (485% non-Hispanic White) was similar to that of the patients in this study (N ¼ 169) and (2) phase II of the Third National Health and Nutrition Examination Survey (NHANES II), conducted from 1992 to 1994 (N ¼ 5171 adults). 40,41 Expected values for CPS alleles were previously determined in a general population sample from Tennessee by Summar et al 33,34 The Cuzick nonparametric test, a modification of the Wilcoxon rank-sum test, was used to assess the trend in risk of HVOD (or other morbid outcomes) across ordered HFE C282Y categories. 42 The effect of the CPS genotype (A allele) on risk of HVOD across C282Y genotypes was assessed by stratified analysis, since an odds ratio for HVOD could not be computed by logistic regression for the AA genotype (no HVOD outcomes).…”

Section: Discussionmentioning

confidence: 99%

The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation

Kallianpur

Hall

Yadav

et al. 2005

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:Hepatic veno-occlusive disease (HVOD) is a serious complication of hematopoietic stem cell transplantation (HSCT). Since the liver is a major site of iron deposition in HFE-associated hemochromatosis, and iron has oxidative toxicity, we hypothesized that HFE genotype might influence the risk of HVOD after myeloablative HSCT. We determined HFE genotypes in 166 HSCT recipients who were evaluated prospectively for HVOD. We also tested whether a common variant of the rate-limiting urea cycle enzyme, carbamyl-phosphate synthetase (CPS), previously observed to protect against HVOD in this cohort, modified the effect of HFE genotype. Risk of HVOD was significantly higher in carriers of at least one C282Y allele (RR ¼ 3.7, 95% CI 1.2-12.1) and increased progressively with C282Y allelic dose (RR ¼ 1.7, 95% CI 0.4-6.8 in heterozygotes; RR ¼ 8.6, 95% CI 1.5-48.5 in homozygotes). The CPS A allele, which encodes a more efficient urea cycle enzyme, reduced the risk of HVOD associated with HFE C282Y. We conclude that HFE C282Y is a risk factor for HVOD and that CPS polymorphisms may counteract its adverse effects. Knowledge of these genotypes and monitoring of iron stores may facilitate risk-stratification and testing of strategies to prevent HVOD, such as iron chelation and pharmacologic support of the urea cycle.

show abstract

Section: Discussionmentioning

confidence: 99%

The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation

Kallianpur

Hall

Yadav

et al. 2005

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…Enzyme activity and mutation analysis are necessary for a correct diagnosis [31]. However, due to the large size of the gene located on chromosome 2, and the heterogeneity of the mutant alleles, functional characterization of mutations may be necessary to determine causality [32][33][34].…”

Section: Carbamyl Phosphate Synthetase Imentioning

confidence: 99%

Contrasting features of urea cycle disorders in human patients and knockout mouse models

Deignan

Cederbaum

Grody

2008

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

The urea cycle exists for the removal of excess nitrogen from the body. Six separate enzymes comprise the urea cycle, and a deficiency in any one of them causes a urea cycle disorder (UCD) in humans. Arginase is the only urea cycle enzyme with an alternate isoform, though no known human disorder currently exists due to a deficiency in the second isoform. While all of the UCDs usually present with hyperammonemia in the first few days to months of life, most disorders are distinguished by a characteristic profile of plasma amino acid alterations that can be utilized for diagnosis. While enzyme assay is possible, an analysis of the underlying mutation is preferable for an accurate diagnosis. Mouse models for each of the urea cycle disorders exist (with the exception of NAGS deficiency), and for almost all of them, their clinical and biochemical phenotypes rather closely resemble the phenotypes seen in human patients. Consequently, all of the current mouse models are highly useful for future research into novel pharmacological and dietary treatments and gene therapy protocols for the management of urea cycle disorders.

show abstract

“…[20][21][22] A common SNP in the CPSI gene causes the substitution of asparagine (Asn) for threonine (Thr) at position 1405 (T1405N) in the critical cofactor-binding domain of the enzyme. 23 Summar et al studied urea cycle function and the prevalence of this SNP in relation to HVOD, ALI, and oxidant stress in 200 patients undergoing myeloablative HSCT at Vanderbilt Medical Center. Both toxicities were strictly defined and determined prospectively, before genetic testing.…”

Section: Hepatic Veno-occlusive Disease and Acute Lung Injurymentioning

confidence: 99%

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

Kallianpur

2004

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:The occurrence of toxic complications following hematopoietic stem cell transplantation (HSCT) is highly variable and dependent on a multitude of host, donor, and treatment factors. The increasingly broad indications for HSCT and the need to provide this treatment option to older and/or more debilitated patients emphasizes the importance of refining our methods of predicting and ameliorating these toxicities. Late complications (occurring after day 100) also pose a threat to quality of life after HSCT. Genetic polymorphisms in key molecular pathways in the host are likely to contribute significantly to the observed variability in the development HSCT-associated complications. Hepatic veno-occlusive disease and acute lung injury, two of the most serious organ toxicities that occur, represent useful paradigms for the identification of genetic polymorphisms in enzyme systems that modulate local and systemic responses to oxidant stress during transplant conditioning therapy. Ongoing studies in this area are providing clues to the prevention of adverse clinical outcomes based on the genetic milieu. This review of studies in HSCT that explore genetic risk factors for transplant complications indicates that significant progress is being made in this rapidly evolving area. However, further large-scale clinical and translational studies are needed before genomic screening can be widely used to individualize treatment. Bone Marrow Transplantation (2005) Clinicians are continually challenged by the need to predict the responses of individual patients to potentially toxic treatments. The increasing promise of cure for patients who undergo hematopoietic stem cell transplantation (HSCT) for life-threatening disorders is overshadowed by the very real threat of short-term, often fatal, complications resulting from the transplant regimen and graft-versushost disease (GVHD). However, significant variation is observed between similarly treated individuals in the development of complications. It is an appealing concept, therefore, and one to which many clinicians now subscribe, that a significant portion of this variability has a genetic basis. Identifying important genetic variables will allow for better prediction of HSCT-related outcomes, and in the process of identifying these susceptibilities, it may also be possible to gain sufficient knowledge of the underlying pathophysiology of these toxicities to develop targeted interventions.This review will focus on genomic screening of the host for the prediction of specific complications, touching briefly on selected donor factors. Other rapidly evolving areas that are not covered include molecular genetic testing to predict graft failure and disease relapse after HSCT. The role of clinical and biochemical risk factors in the pre-transplant evaluation of HSCT candidates has also been reviewed recently in this journal. 1 Importance of context-dependent genetic effectsThe study of uncommon disease-associated mutations has been invaluable to our understanding of basic pathophy...

show abstract

Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene

Cited by 52 publications

References 14 publications

The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation

The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation

Contrasting features of urea cycle disorders in human patients and knockout mouse models

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

Contact Info

Product

Resources

About