Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.44 (AGT)
770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Finding the genetic determinants of intermediate quantitative traits, such as serum creatinine and urea, might aid in finding the determinants of disease phenotypes, such as renal failure, that are, in part, defined according to threshold values imposed upon such traits. We evaluated the association between common variation in the gene encoding angiotensinogen, AGT, and the serum concentrations of creatinine and urea in non-diabetic Canadian Oji-Cree. We determined genotypes of the AGT codon 235 polymorphism among 502 non-diabetic Oji-Cree. We used multivariate analysis of variance to identify significant determinants of variation in serum concentrations of creatinine and urea and of systolic and diastolic blood pressure. We found significant associations between the AGT codon 235 genotype and serum concentrations of creatinine and urea (p = 0.017 and 0.049, respectively) and systolic blood pressure (p = 0.041). Compared with subjects with the other two genotypes, homozygotes for AGT T235/T235 had significantly lower serum concentrations of creatinine and urea and significantly higher mean systolic blood pressure. The findings suggest that the AGT T235 allele is a determinant of intermediate traits related to renal function in these aboriginal Canadians.
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PMID:Association between AGT codon 235 polymorphism and variation in serum concentrations of creatinine and urea in Canadian Oji-Cree. 1045 Aug 60

Primary hyperoxaluria type 1 (PH1) is caused by deficiency of peroxisomal alanine-glyoxylate aminotransferase which is in humans exclusively expressed in liver cells. The disease is inherited as an autosomal recessive trait, and initial symptoms usually occur in early childhood. Up to the age of 25 years, 90% of the patients are symptomatic, and many patients develop end-stage renal failure. Pronounced medical care is necessary in PH1 patients to prevent generalized oxalosis with complications due to bone disease and peripheral gangrene. The rather short survival of patients on hemodialysis is caused by sudden arrhythmias and heart block. As no dialysis procedure is able to remove the daily produced oxalate, early transplantation is mandatory. Our 45-year-old patient is remarkable on the basis of the late manifestations of PH1. The diagnosis was delayed by unspecific symptoms of nephrolithiasis with recurrent pyelonephritis. Clinical course and diagnostic cornerstones of primary hyperoxaluria are outlined. The principles of conservative treatment and experiences with dialysis and transplantation are discussed.
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PMID:Primary hyperoxaluria type 1 causing end-stage renal disease in a 45-year-old patient. 1117 30

Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder in which deficiency of the liver enzyme AGT leads to renal failure and systemic oxalosis. Timely, combined cadaveric liver-kidney transplantation (LKT) is recommended for end-stage renal failure (ESRF) caused by PH1; however, the shortage of cadaveric organs has generated enthusiasm for living-related transplantation in years. Recently, successful sequential LKT from the same living donor has been reported in a child with PH1. We present a sister-to-brother simultaneous LKT in a pediatric patient who suffered from PH1 with ESRF. Twelve months after transplantation, his daily urine oxalate excretion was decreased from 160 mg to 19.5 mg with normal liver and renal allograft functions. In addition to the well-known advantages of living organ transplantation, simultaneous LKT may facilitate early postoperative hemodynamic stability and may induce immunotolerance and allow for low-dose immunosuppression.
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PMID:Primary hyperoxaluria: simultaneous combined liver and kidney transplantation from a living related donor. 1268 98

Primary hyperoxaluria (PH1) is a condition caused by a hepatic-based enzyme defect which can lead to renal failure due to oxalate stone disease, obstructive uropathy and nephrocalcinosis. It has been shown that the underlying metabolic defect can be corrected by liver transplantation and in most cases (renal failure having already occurred) is accompanied by a kidney graft. This paper describes the current results of 127 liver transplants performed in 117 patients over a 20-year period from 1984 to 2004 in 35 European centres. The mean age at onset of symptoms was 5.6 +/- 7.8 years and the mean age at which a diagnosis was made was 8.8 +/- 9.5 years. The diagnosis was confirmed by liver biopsy proven decreased AGT activity in 68% of cases, hyperoxaluria in 74%, hyperglycolicaciduria in 37% and hyperoxalaemia in 50%. Patients were transplanted at a mean age of 16.5 +/- 11.4 years following a period of dialysis of 3.2 +/- 3.2 years (range 0-14.4 years). 1-, 5- and 10-year patient survival values were 86, 80 and 69%, respectively, and liver graft survival rates of 80, 72 and 60% at the same time intervals. There have been 27 deaths and 10 liver retransplants have been carried out. Patient outcomes are improved when prolonged periods on dialysis and the complications of systemic oxalosis have not occurred.
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PMID:A 20-year experience of combined liver/kidney transplantation for primary hyperoxaluria (PH1): the European PH1 transplant registry experience 1984-2004. 1596 48

We report herein a domino orthotopic liver transplantation (LT), from a 38-year-old woman undergoing liver-kidney transplantation (LKT) for primary hyperoxaluria type I (PH1) to a recipient with cirrhosis and hepatocellular carcinoma. Delayed onset of PH1 and renal failure and 10% residual alanine-glyoxylate aminotransferase (AGT) activity in domino liver justified its use for domino procedure. The clinical course after LKT was similar to that described in other series, including ours. Renal function started promptly and maintained despite sustained hyperoxaluria from dissolution of oxalotic deposits. Conversely, the domino recipient manifested severe hyperoxaluria and developed nephrolithiasis and renal insufficiency with rapid progression over 2 months. A new LT resulted in slow decrease of oxaluria and improvement of renal function. Therefore, PH1 behaved quite differently in these two patients, leading us to conclude that domino LT using livers from PH1 patients should be considered very carefully, only as a bridge to definitive LT in recipients with critical clinical conditions.
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PMID:Severe course of primary hyperoxaluria and renal failure after domino hepatic transplantation. 1609 18

Genetic disorders of mineral metabolism cause urolithiasis, renal disease, and osteodystrophy. Most are rare, such that the full spectrum of clinical expression is difficult to appreciate. Diagnosis is further complicated by overlap of clinical features. Dent's disease and primary hyperoxaluria, inherited causes of calcium urolithiasis, are both associated with nephrocalcinosis and urolithiasis in early childhood and renal failure that can occur at any age but is seen more often in adulthood. Bone disease is an inconsistent feature of each. Dent's disease is caused by mutations of the CLCN-5 gene with impaired kidney-specific CLC-5 chloride channel expression in the proximal tubule, thick ascending limb of Henle, and the collecting ducts. Resulting hypercalciuria and proximal tubule dysfunction, including phosphate wasting, are primarily responsible for the clinical manifestations. Low-molecular-weight proteinuria is characteristic. Definitive diagnosis is made by DNA mutation analysis. Primary hyperoxaluria, type I, is due to mutations of the AGXT gene leading to deficient hepatic alanine-glyoxylate aminotransferase activity. Marked overproduction of oxalate by hepatic cells results in the hyperoxaluria responsible for clinical features. Definitive diagnosis is by liver biopsy with measurement of enzyme activity, with DNA mutation analysis used increasingly as mutations and their frequency are defined. These disorders of calcium urolithiasis illustrate the value of molecular medicine for diagnosis and the promise it provides for innovative and more effective future treatments.
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PMID:Stones, bones, and heredity. 1680 Nov 62

PH1 is a metabolic disorder characterized by urolithiasis and the accumulation of oxalate crystals in the kidneys and other organs. Although patients often first present with renal failure, PH1 results from a deficiency of the hepatic peroxisomal enzyme AGT. Ultimately only liver transplantation will cure the underlying metabolic defect. Herein, we report the case of a three-month-old male infant diagnosed with PH and treated using a combined liver and en bloc-kidney transplant from a single donor. At the time of transplant, the patient was 11 months old and weighed 7.9 kg. He received a full size liver graft and en bloc kidneys from a two-yr-old donor. At 36 months post-transplant, the patient is steadily growing with normal renal and hepatic function. This is one of the first reports of successful liver and en bloc-kidney transplantation with abdominal compartment expansion by PTFE for the infantile form of PH1 in a high risk child before one yr of age. Prompt diagnosis and early referral to a specialized center for liver and kidney replacement offer the best chance for survival for infants with this otherwise fatal disease.
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PMID:Successful outcome after early combined liver and en bloc-kidney transplant in an infant with primary hyperoxaluria type 1: a case report. 1968 42

PH1 is an inborn error of the metabolism in which a functional deficiency of the liver-specific peroxisomal enzyme, AGT, causes hyperoxaluria and hyperglycolic aciduria. Infantile PH1 is the most aggressive form of this disease, leading to early nephrocalcinosis, systemic oxalosis, and end-stage renal failure. Infantile PH1 is rapidly fatal in children unless timely liver-kidney transplantation is performed to correct both the hepatic enzyme defect and the renal end-organ damage. The surgical procedure can be further complicated in infants and young children, who are at higher risk for vascular anomalies, such as IVC thrombosis. Although recently a limited number of children with IVC thrombosis have underwent successful kidney transplantation, successful multi-organ transplantation in a child with complete IVC thrombosis is quite rare. We report here the interesting and technically difficult case of a three-yr-old girl with a complete thrombosis of the IVC, who was the recipient of combined split liver and kidney transplantation for infantile PH1. Although initial delayed renal graft function with mild-to-moderate acute rejection was observed, the patient rapidly regained renal function after steroid boluses, and was soon hemodialysis-independent, with good diuresis. Serum and plasma oxalate levels progressively decreased; although, to date they are still above normal. Hepatic and renal function indices were at, or approaching, normal values when the patient was discharged 15-wk post-transplant, and the patient continues to do well, with close and frequent follow-up. This is the first report of a successful double-organ transplant in a pediatric patient presenting with infantile PH1 complicated by complete IVC thrombosis.
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PMID:Combined split liver and kidney transplantation in a three-year-old child with primary hyperoxaluria type 1 and complete thrombosis of the inferior vena cava. 1979 27

Mutations in the alanine-glyoxylate aminotransferase gene (AGXT) are responsible for primary hyperoxaluria type I, a rare disease characterized by excessive hepatic oxalate production that leads to renal failure. A deeper understanding of the changes in the metabolic pathways secondary to the lack of AGXT expression is needed in order to explore substrate depletion as a therapeutic strategy to limit oxalate production in primary hyperoxaluria type I. We have developed an Agxt knockout (AgxtKO) mouse that reproduces some key features of primary hyperoxaluria type I. To improve our understanding of the metabolic adjustments subsequent to AGXT deficiency, we performed a proteomic analysis of the changes in expression levels of various subcellular fractions of liver and kidney metabolism linked to the lack of AGXT. In this article, we report specific changes in the liver and kidney proteome of AgxtKO mice that point to significant variations in gluconeogenesis, glycolysis and fatty acid pathways.
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PMID:Differential expression of liver and kidney proteins in a mouse model for primary hyperoxaluria type I. 2097 70

Primary hyperoxaluria type I (PH1) is an inborn error of metabolism caused by deficiency of the hepatic enzyme alanine-glyoxylate aminotransferase (AGXT or AGT) which leads to overproduction of oxalate by the liver and subsequent urolithiasis and renal failure. The current therapy largely depends on liver transplantation, which is associated with significant morbidity and mortality. To explore an alternative treatment, we used somatic gene transfer in a mouse genetic model for PH1 (Agxt1KO). Recombinant adeno-associated virus (AAV) vectors containing the human AGXT complementary DNA (cDNA) were pseudotyped with capsids from either serotype 8 or 5, and delivered to the livers of Agxt1KO mice via the tail vein. Both AAV8-AGXT and AAV5-AGXT vectors were able to reduce oxaluria to normal levels. In addition, treated mice showed blunted increase of oxaluria after challenge with ethylene glycol (EG), a glyoxylate precursor. In mice, AGT enzyme activity in whole liver extracts were restored to normal without hepatic toxicity nor immunogenicity for the 50 day follow-up. In summary, this study demonstrates the correction of primary hyperoxaluria in mice treated with either AAV5 or AAV8 vectors.
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PMID:Phenotypic correction of a mouse model for primary hyperoxaluria with adeno-associated virus gene transfer. 2111 25


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