Two independent mutational events in the loss of urate oxidase during hominoid evolution

Wu, Xiangwei; Muzny, D. M.; Lee, Cheng‐Chi; Caskey, C. Thomas

doi:10.1007/bf00163854

Cited by 465 publications

(331 citation statements)

References 22 publications

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“…relatively large amounts of UA (26,27). However, the urate oxidase gene has been inactivated in higher order primates, and their serum UA levels are substantially higher (44,45). This has been the stimulus of considerable speculation as to the importance of UA to human evolution (e.g., 46 -48).…”

Section: Discussionmentioning

confidence: 99%

The Central Nervous System Inflammatory Response to Neurotropic Virus Infection Is Peroxynitrite Dependent

Hooper

Kean

Scott

et al. 2001

The Journal of Immunology

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We have recently demonstrated that increased blood-CNS barrier permeability and CNS inflammation in a conventional mouse model of experimental allergic encephalomyelitis are dependent upon the production of peroxynitrite (ONOO−), a product of the free radicals NO· and superoxide (O2·−). To determine whether this is a reflection of the physiological contribution of ONOO− to an immune response against a neurotropic pathogen, we have assessed the effects on adult rats acutely infected with Borna disease virus (BDV) of administration of uric acid (UA), an inhibitor of select chemical reactions associated with ONOO−. The pathogenesis of acute Borna disease in immunocompetent adult rats results from the immune response to the neurotropic BDV, rather than the direct effects of BDV infection of neurons. An important stage in the BDV-specific neuroimmune response is the invasion of inflammatory cells into the CNS. UA treatment inhibited the onset of clinical disease, and prevented the elevated blood-brain barrier permeability as well as CNS inflammation seen in control-treated BDV-infected rats. The replication and spread of BDV in the CNS were unchanged by the administration of UA, and only minimal effects on the immune response to BDV Ags were observed. These results indicate that the CNS inflammatory response to neurotropic virus infection is likely to be dependent upon the activity of ONOO− or its products on the blood-brain barrier.

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Section: Discussionmentioning

confidence: 99%

The Central Nervous System Inflammatory Response to Neurotropic Virus Infection Is Peroxynitrite Dependent

Hooper

Kean

Scott

et al. 2001

The Journal of Immunology

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“…Most of the mammalian species possess the urate-degrading enzyme urate oxidase and have rather low concentrations of plasma urate. The human genome contains the sequence for urate oxidase, but the gene has lost its function because of at least 3 deleterious mutations (1,2). Because of the deficiency of urate oxidase in the species, humans tend to show plasma urate levels that are over the limit of solubility, and some individuals with serum urate concentrations Ͼ7 mg/dl develop gout.…”

Section: To the Editormentioning

confidence: 99%

A common mutation in an organic anion transporter gene, SLC22A12, is a suppressing factor for the development of gout

Taniguchi¹,

Urano²,

Yamanaka³

et al. 2005

Arthritis & Rheumatism

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“…This loss of enzymatic function has led to uniquely high serum urate levels compared with other mammals. 3 In humans, several factors can lead to increased levels of serum urate (hyperuricemia) as a result of elevated generation and decreased excretion. These include high dietary intake of purines, high fructose intake, alcohol consumption, impaired renal excretion of urate and defective purine metabolism due to genetic disorders, such as hypoxanthine guanine phosphoribosyltransferase deficiency.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide scan identifies a quantitative trait locus at 4p15.3 for serum urate

et al. 2010

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Elevated serum urate levels lead to gout and are associated with hypertension, metabolic syndrome, type 2 diabetes and cardiovascular diseases. The purpose of this study was to identify evidence for genetic linkage with serum urate and to determine whether variation within positional candidate genes is associated with serum urate levels in a non-European population. Genetic linkage analysis and single nucleotide polymorphism (SNP) genotyping was performed in a large family pedigree cohort from Mauritius. We assessed associations between serum urate levels and 97 SNPs in a positional candidate gene, SLC2A9. A genome-wide scan identified a new region with evidence for linkage for serum urate at 4p15.3. SNP genotyping identified significant association between six SNP variants in SLC2A9 and serum urate levels. Allelic and gender-based effects were noted for several SNPs. Significant correlations were also observed between serum urate levels and individual components of metabolic syndrome. Our study results implicate genetic variation in SLC2A9 in influencing levels of serum urate over a broad range of values in a large Mauritian family cohort. INTRODUCTIONHyperuricemia is associated with, and often precedes, several cardiovascular disease (CVD) risk factors including hypertension, inflammation, dyslipidemia, kidney disease, obesity, insulin resistance and metabolic syndrome. 1 Furthermore, increased serum urate has been shown to be an independent risk factor for CVD in high-risk individuals. 2 Urate (uric acid) is the end product of purine metabolism in humans due to the evolutionary loss of hepatic urate oxidase (uricase) activity. This loss of enzymatic function has led to uniquely high serum urate levels compared with other mammals. 3 In humans, several factors can lead to increased levels of serum urate (hyperuricemia) as a result of elevated generation and decreased excretion. These include high dietary intake of purines, high fructose intake, alcohol consumption, impaired renal excretion of urate and defective purine metabolism due to genetic disorders, such as hypoxanthine guanine phosphoribosyltransferase deficiency. 4 Given the significant health consequences of variation in serum urate, we sought to understand the mechanisms controlling its levels. In this article, we present the results of our genetic linkage analysis that has identified a novel quantitative trait locus influencing serum urate levels at 4p15.3. Notably, recent genome-wide association studies have identified a strong positional candidate gene, SLC2A9, in this region. [5][6][7] In this study, we aim to characterize the genetic variation contributing to the linkage signal observed at 4p15.3 by single nucleotide polymorphism (SNP) genotyping the positional candidate SLC2A9 in the Mauritius Family Study population. The Mauritius Family Study focuses on large family pedigrees from a subset of the

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Two independent mutational events in the loss of urate oxidase during hominoid evolution

Cited by 465 publications

References 22 publications

The Central Nervous System Inflammatory Response to Neurotropic Virus Infection Is Peroxynitrite Dependent

The Central Nervous System Inflammatory Response to Neurotropic Virus Infection Is Peroxynitrite Dependent

A common mutation in an organic anion transporter gene, SLC22A12, is a suppressing factor for the development of gout

Genome-wide scan identifies a quantitative trait locus at 4p15.3 for serum urate

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