Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.44 (AGT)
 770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nephrogenic diabetes insipidus (NDI) is a rare disease characterized by renal inability to respond properly to arginine vasopressin due to mutations in the vasopressin type 2 receptor (V2(R)) gene in affected kindreds. In most kindreds thus far reported, the mode of inheritance follows an X chromosome-linked recessive pattern although autosomal-dominant and autosomal-recessive modes of inheritance have also been described. Studies demonstrating mutations in the V2(R) gene in affected kindreds that modify the receptor structure, resulting in a dys- or nonfunctional receptor have been described, but phenotypically indistinguishable NDI patients with a structurally normal V2(R) gene have also been reported. In the present study, we analyzed exon 3 of the V2(R) gene in 20 unrelated individuals by direct sequencing. A C-->T alteration in the third position of codon 331 (AGC-->AGT), which did not alter the encoded amino acid, was found in nine individuals, including two unrelated patients with NDI. Taken together, these observations emphasize the molecular heterogeneity of a phenotypically homogeneous syndrome.
 ...
PMID:A novel polymorphism in the coding region of the vasopressin type 2 receptor gene. 925 62

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.
 ...
PMID:Differential expression of liver and kidney proteins in a mouse model for primary hyperoxaluria type I. 2097 70

Primary hyperoxaluria (PH) occurs due to an autosomal recessive hereditary disorder of the metabolism of glyoxylate, which causes excessive oxalate production. The most frequent and serious disorder is due to enzyme deficit of alanine-glyoxylate aminotransferase (PH type I) specific to hepatic peroxisome. As oxalate is not metabolised in humans and is excreted through the kidneys, the kidney is the first organ affected, causing recurrent lithiasis, nephrocalcinosis and early renal failure. With advance of renal failure, particularly in patients on haemodialysis (HD), calcium oxalate is massively deposited in tissues, which is known as oxalosis. Diagnosis is based on family history, the presence of urolithiasis and/or nephrocalcinosis, hyperoxaluria, oxalate deposits in tissue forming granulomas, molecular analysis of DNA and enzyme analysis if applicable. High diagnostic suspicion is required; therefore, unfortunately, in many cases it is diagnosed after its recurrence following kidney transplantation. Conservative management of this disease (high liquid intake, pyridoxine and crystallisation inhibitors) needs to be adopted early in order to delay kidney damage. Treatment by dialysis is ineffective in treating excess oxalate. After the kidney transplant, we normally observe a rapid appearance of oxalate deposits in the graft and the results of this technique are discouraging, with very few exceptions. Pre-emptive liver transplantation, or simultaneous liver and kidney transplants when there is already irreversible damage to the kidney, is the treatment of choice to treat the underlying disease and suppress oxalate overproduction. Given its condition as a rare disease and its genetic and clinical heterogeneity, it is not possible to gain evidence through randomised clinical trials. As a result, the recommendations are established by groups of experts based on publications of renowned scientific rigour. In this regard, a group of European experts (OxalEurope) has drawn up recommendations for diagnosis and treatment, which were published in 2012.
...
PMID:Primary hyperoxaluria. 2479 59

Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.
 ...
PMID:An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria. 2953 12

Primary hyperoxaluria type I (PH1) is a rare disease caused by the deficit of liver alanine-glyoxylate aminotransferase (AGT). AGT prevents oxalate formation by converting peroxisomal glyoxylate to glycine. When the enzyme is deficient, progressive calcium oxalate stones deposit first in the urinary tract and then at the systemic level. Pyridoxal 5'-phosphate (PLP), the AGT coenzyme, exerts a chaperone role by promoting dimerization, as demonstrated by studies at protein and cellular level. Thus, variants showing a destabilized dimeric structure should, in principle, be responsive to vitamin B6, a precursor of PLP. However, models to predict the extent of responsiveness of each variant are missing. We examined the effects of pathogenic interfacial mutations by combining bioinformatic predictions with molecular and cellular studies on selected variants (R36H, G42E, I56N, G63R, and G216R), in both their holo- (i.e., with bound PLP) and apo- (i.e., without bound PLP) form. We found that all variants displayed structural alterations mainly related to the apoform and consisting of an altered tertiary and quaternary structure. G216R also shows a strongly reduced catalytic efficiency. Moreover, all but G216R respond to vitamin B6, as shown by their increased specific activity and expression level in a cellular disease model. A global analysis of data unraveled a possible inverse correlation between the degree of destabilization/misfolding induced by a mutation and the extent of B6 responsiveness. These results provide a first explanation of factors influencing B6 response in PH1, a model possibly valuable for other rare diseases caused by protein deficits.
 ...
PMID:Correlation between the molecular effects of mutations at the dimer interface of alanine-glyoxylate aminotransferase leading to primary hyperoxaluria type I and the cellular response to vitamin B6. 2911 Jan 80