Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal hypouricemia is an inherited disorder characterized by impaired renal urate (uric acid) reabsorption and subsequent low serum urate levels, with severe complications such as exercise-induced acute renal failure and nephrolithiasis. We previously identified SLC22A12, also known as URAT1, as a causative gene of renal hypouricemia. However, hypouricemic patients without URAT1 mutations, as well as genome-wide association studies between urate and SLC2A9 (also called GLUT9), imply that GLUT9 could be another causative gene of renal hypouricemia. With a large human database, we identified two loss-of-function heterozygous mutations in GLUT9, which occur in the highly conserved "sugar transport proteins signatures 1/2." Both mutations result in loss of positive charges, one of which is reported to be an important membrane topology determinant. The oocyte expression study revealed that both GLUT9 isoforms showed high urate transport activities, whereas the mutated GLUT9 isoforms markedly reduced them. Our findings, together with previous reports on GLUT9 localization, suggest that these GLUT9 mutations cause renal hypouricemia by their decreased urate reabsorption on both sides of the renal proximal tubules. These findings also enable us to propose a physiological model of the renal urate reabsorption in which GLUT9 regulates serum urate levels in humans and can be a promising therapeutic target for gout and related cardiovascular diseases.
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PMID:Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. 1902 95

A deficiency in hypoxanthine guanine phosphoribosyltransferase (HPRT) activity leads to overproduction of uric acid. According to the degree of enzymatic deficiency, a large spectrum of neurologic features can also be observed, ranging from mild or no neurologic involvement to complete Lesch-Nyhan disease. Herein, we describe a patient with hyperuricemia, juvenile-onset gouty arthritis, nephrolithiasis, and mild neurologic symptoms, attributed to a newly identified variant of the hprt gene, c.596T>G, resulting in the amino acid change p.F199C. Residual HPRT activity (8%) protected against severe neurologic involvement in this patient. Modeling of the mutated protein was used to predict the mechanisms that led to partial enzymatic activity. Careful neurologic examination is warranted in juvenile and middle-aged patients with gout, in order to detect mild symptoms that may lead to a diagnosis of HPRT deficiency.
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PMID:Severe gouty arthritis and mild neurologic symptoms due to F199C, a newly identified variant of the hypoxanthine guanine phosphoribosyltransferase. 1956 99

Elevated plasma urate levels are associated with metabolic, cardiovascular, and renal diseases. Urate may also form crystals, which can be deposited in joints causing gout and in kidney tubules inducing nephrolithiasis. In mice, plasma urate levels are controlled by hepatic breakdown, as well as, by incompletely understood renal processes of reabsorption and secretion. Here, we investigated the role of the recently identified urate transporter, Glut9, in the physiological control of urate homeostasis using mice with systemic or liver-specific inactivation of the Glut9 gene. We show that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron. Mice with systemic knockout of Glut9 display moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex, as well as, mild renal insufficiency. In contrast, liver-specific inactivation of the Glut9 gene in adult mice leads to severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. Together, our data show that Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.
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PMID:Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy. 1970 26

Hereditary hypouricemia may result from mutations in the renal tubular uric acid transporter URAT1. Whether mutation of other uric acid transporters produces a similar phenotype is unknown. We studied two families who had severe hereditary hypouricemia and did not have a URAT1 defect. We performed a genome-wide homozygosity screen and linkage analysis and identified the candidate gene SLC2A9, which encodes the glucose transporter 9 (GLUT9). Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. In vitro, the L75R mutation dramatically impaired transport of uric acid. The mean concentration of serum uric acid of seven homozygous individuals was 0.17 +/- 0.2 mg/dl, and all had a fractional excretion of uric acid >150%. Three individuals had nephrolithiasis, and three had a history of exercise-induced acute renal failure. In conclusion, homozygous loss-of-function mutations of GLUT9 cause a total defect of uric acid absorption, leading to severe renal hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. In addition to clarifying renal handling of uric acid, our findings may provide a better understanding of the pathophysiology of acute renal failure, nephrolithiasis, hyperuricemia, and gout.
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PMID:Homozygous SLC2A9 mutations cause severe renal hypouricemia. 1992 91

Hyperuricemia is a condition of defective purine metabolism characterized with elevated serum uric acid (UA) level that further leads to gout and gouty nephrolithiasis disorders. Gout is a world wide distributed rheumatic disease comprises 1% of the total population and still is in increasing state. One of the factors contributing to overproduction of UA is the hydroxylation of xanthine catalyzed by xanthine oxidase (XO). In the present study, 3D modeling of Arthrobacter sp. XL26 (xodB) protein was performed by comparative modeling approach using Rhodobacter capsulatus XDH (PDB ID: 2W3sF) as template in SWISS-MODEL, Geno3D and MODELLER program server. The best model was selected based on overall stereochemical quality (Procheck, PROSA, GenThreader), energy minimized, refined and used for active site characterization in BioMed CAChe workspace. The enzyme-inhibitor interaction was studied by docking to screen the possible inhibitors and application of model in design and development of anti-gout agents.
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PMID:Homology modeling and docking study of xanthine oxidase of Arthrobacter sp. XL26. 2040 78

In contrast to large GWA studies based on thousands of individuals and large meta-analyses combining GWAS results, we analyzed a small case/control sample for uric acid nephrolithiasis. Our cohort of closely related individuals is derived from a small, genetically isolated village in Sardinia, with well-characterized genealogical data linking the extant population up to the 16(th) century. It is expected that the number of risk alleles involved in complex disorders is smaller in isolated founder populations than in more diverse populations, and the power to detect association with complex traits may be increased when related, homogeneous affected individuals are selected, as they are more likely to be enriched with and share specific risk variants than are unrelated, affected individuals from the general population. When related individuals are included in an association study, correlations among relatives must be accurately taken into account to ensure validity of the results. A recently proposed association method uses an empirical genotypic covariance matrix estimated from genome-screen data to allow for additional population structure and cryptic relatedness that may not be captured by the genealogical data. We apply the method to our data, and we also investigate the properties of the method, as well as other association methods, in our highly inbred population, as previous applications were to outbred samples. The more promising regions identified in our initial study in the genetic isolate were then further investigated in an independent sample collected from the Italian population. Among the loci that showed association in this study, we observed evidence of a possible involvement of the region encompassing the gene LRRC16A, already associated to serum uric acid levels in a large meta-analysis of 14 GWAS, suggesting that this locus might lead a pathway for uric acid metabolism that may be involved in gout as well as in nephrolithiasis.
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PMID:Application of a new method for GWAS in a related case/control sample with known pedigree structure: identification of new loci for nephrolithiasis. 2128 82

Ceftriaxone is known to cause biliary pseudolithiasis and, rarely, nephrolithiasis. When used in neonates receiving intravenous calcium, fatal lung and kidney calcifications occur. There is no satisfactory explanation for the pseudolithiasis, and the mechanism of stone formation remains unknown. Herein, we report a child with acute urinary retention (AUR) secondary to ceftriaxone therapy. The AUR developed on the second hospital day. The urinary excretion of uric acid was elevated. In retrospect, there was a positive paternal family history of gout and stones. A positive family history of gout or stones is a pointer to the possibility of AUR or urolithiasis in patients on treatment with ceftriaxone. If urinary symptoms develop, it is worth checking for crystalluria. This will avoid many unnecessary investigations and procedures.
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PMID:Acute urine retention induced by ceftriaxone. 2208 89

Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a spectrum of clinical phenotypes. All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. In between these two extremes is a continuous spectrum of phenotypes with varying degrees of motor and cognitive handicap but no self-injurious behavior. The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. The pathogenesis of the neurobehavioral problems is less well-understood, and effective treatments for them are lacking.
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PMID:Update on the phenotypic spectrum of Lesch-Nyhan disease and its attenuated variants. 2219 33

With considering serum concentration of the uric acid in humans we are observing hyperuricemia and possible gout development. Many epidemiological studies have shown the relationship between the uric acid and different disorders such are obesity, metabolic syndrome, hypertension and coronary artery disease. Clinicians and investigators recognized serum uric acid concentration as very important diagnostic and prognostic factor of many multifactorial disorders. This review presented few clinical conditions which are not directly related to uric acid, but the concentrations of uric acid might have a great impact in observing, monitoring, prognosis and therapy of such disorders. Uric acid is recognized as a marker of oxidative stress. Production of the uric acid includes enzyme xanthine oxidase which is involved in producing of radical-oxigen species (ROS). As by-products ROS have a significant role in the increased vascular oxidative stress and might be involved in atherogenesis. Uric acid may inhibit endothelial function by inhibition of nitric oxide-function under conditions of oxidative stress. Down regulation of nitric oxide and induction of endothelial dysfunction might also be involved in pathogenesis of hypertension. The most important and well evidenced is possible predictive role of uric acid in predicting short-term outcome (mortality) in acute myocardial infarction (AMI) patients and stroke. Nephrolithiasis of uric acid origin is significantly more common among patients with the metabolic syndrome and obesity. On contrary to this, uric acid also acts is an "antioxidant", a free radical scavenger and a chelator of transitional metal ions which are converted to poorly reactive forms.
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PMID:Uric acid as one of the important factors in multifactorial disorders--facts and controversies. 2238 20

The aim of this study was to determine the prevalence of simple renal cysts in gout patients and evaluate associated risk factors for its development. Hundred and forty-six patients followed at our outpatient Gout Unit and 47 sex- and age-matched healthy kidney donors who had undergone routine renal ultrasonography, using a static gray scale and real-time B-mode units with a 3.5- or 5.0-MHz transducer, were evaluated for the presence of renal cysts. Demographic and clinical characteristics of gout patients were evaluated considering possible risk factors for the occurrence of simple renal cysts such as age, male gender, hypertension, and renal impairment. The prevalence of simple renal cyst was 26.0 % in gout patients and 10.6 % in control group (P = 0.045). Gout patients with simple renal cysts presented less renal lithiasis than those without this complication (5.2 vs 25.9 %; P = 0.003) in spite of an overall higher frequency of renal stones in gout patients compared to control group (20.5 vs. 6.3 %, P = 0.025). The presence of simple renal cyst in gout was not associated with previously reported factors such as age (P = 0.296), male predominance (P = 0.688), hypertension (P = 0.314), and renal impairment (P = 254). Moreover, no association with disease duration (P = 0.843) or tophi (P = 0.616) was observed. In conclusion, gout patients have an increased prevalence of simple renal cysts associated with a lower occurrence of nephrolithiasis. Whether renal cysts have any protective effect in the development of nephrolithiasis in gout remains to be determined.
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PMID:Increased prevalence of simple renal cysts in patients with gout. 2337 32


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