Variability in Kidney Stone Incidence Between Black and White South Africans: AGT Pro11Leu Polymorphism Is Not a Factor

Theka, Takalani; Rodgers, Allen L.; Webber, Dawn; O’Ryan, Colleen

doi:10.1089/end.2013.0617

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…In the present study, the concentrations of oxalate and glyoxylate were different in cells expressing AGT-mi and AGT-MA only when pyridoxine concentration was below 0.3 μM. Similar urinary oxalate excretions in individuals containing only the major allele or heterozygous for the minor allele have been reported, but the patients’ status regarding pyridoxine was not known [50]. The impact of the minor allele of AGT is expected to be minor at best but may only be of consequence for minor allele homozygotes, especially if the pyridoxine levels are low.…”

Section: Discussionsupporting

confidence: 61%

Effects of alanine:glyoxylate aminotransferase variants and pyridoxine sensitivity on oxalate metabolism in a cell-based cytotoxicity assay

Fargue

Knight

Holmes

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The hereditary kidney stone disease primary hyperoxaluria type 1 (PH1) is caused by a functional deficiency of the liver-specific, peroxisomal, pyridoxal-phosphate-dependent enzyme, alanine:glyoxylate aminotransferase (AGT). One third of PH1 patients, particularly those expressing the p.[(Pro11Leu; Gly170Arg; Ile340Met)] mutant allele, respond clinically to pharmacological doses of pyridoxine. To gain further insight into the metabolic effects of AGT dysfunction in PH1 and the effect of pyridoxine, we established an “indirect” glycolate cytotoxicity assay using CHO cells expressing glycolate oxidase (GO) and various normal and mutant forms of AGT. In cells expressing GO the great majority of glycolate was converted to oxalate and glyoxylate, with the latter causing the greater decrease in cell survival. Co-expression of normal AGTs and some, but not all, mutant AGT variants partially counteracted this cytotoxicity and led to decreased synthesis of oxalate and glyoxylate. Increasing the extracellular pyridoxine up to 0.3 μM led to an increased metabolic effectiveness of normal AGTs and the AGT-Gly170Arg variant. The increased survival seen with AGT-Gly170Arg was paralleled by a 40% decrease in oxalate and glyoxylate levels. These data support the suggestion that the effectiveness of pharmacological doses of pyridoxine results from an improved metabolic effectiveness of AGT; that is the increased rate of transamination of glyoxylate to glycine. The indirect glycolate toxicity assay used in the present study has potential to be used in cell-based drug screening protocols to identify chemotherapeutics that might enhance or decrease the activity and metabolic effectiveness of AGT and GO, respectively, and be useful in the treatment of PH1.

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Section: Discussionsupporting

confidence: 61%

Effects of alanine:glyoxylate aminotransferase variants and pyridoxine sensitivity on oxalate metabolism in a cell-based cytotoxicity assay

Fargue

Knight

Holmes

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Besides pathogenic forms, it is of note that 20% of the Caucasian population express a polymorphic form of AGT1 called minor allele (AGT‐Mi), which differs from the more common major allele (AGT‐Ma) for the P11L and I340M substitutions 15 . AGT‐Mi is not pathogenic per se, and it is not considered a risk factor for idiopathic kidney stone disease 16 . However, some missense mutations in AGT1 are only pathogenic if inherited on the background of the minor allele polymorphism, a form of genetic epistasis 17,18 .…”

Section: Introductionmentioning

confidence: 99%

“…15 AGT-Mi is not pathogenic per se, and it is not considered a risk factor for idiopathic kidney stone disease. 16 However, some missense mutations in AGT1 are only pathogenic if inherited on the background of the minor allele polymorphism, a form of genetic epistasis. 17,18 As compared to AGT-Ma, AGT-Mi displays a slightly reduced catalytic efficiency and thermodynamic stability, as well as increased tendency to aggregation and intracellular degradation.…”

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confidence: 99%

Structural dynamics shape the fitness window of alanine:glyoxylate aminotransferase

et al. 2022

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The conformational landscape of a protein is constantly expanded by genetic variations that have a minimal impact on the function(s) while causing subtle effects on protein structure. The wider the conformational space sampled by these variants, the higher the probabilities to adapt to changes in environmental conditions. However, the probability that a single mutation may result in a pathogenic phenotype also increases. Here we present a paradigmatic example of how protein evolution balances structural stability and dynamics to maximize protein adaptability and preserve protein fitness. We took advantage of known genetic variations of human alanine:glyoxylate aminotransferase (AGT1), which is present as a common major allelic form (AGT‐Ma) and a minor polymorphic form (AGT‐Mi) expressed in 20% of Caucasian population. By integrating crystallographic studies and molecular dynamics simulations, we show that AGT‐Ma is endowed with structurally unstable (frustrated) regions, which become disordered in AGT‐Mi. An in‐depth biochemical characterization of variants from an anticonsensus library, encompassing the frustrated regions, correlates this plasticity to a fitness window defined by AGT‐Ma and AGT‐Mi. Finally, co‐immunoprecipitation analysis suggests that structural frustration in AGT1 could favor additional functions related to protein–protein interactions. These results expand our understanding of protein structural evolution by establishing that naturally occurring genetic variations tip the balance between stability and frustration to maximize the ensemble of conformations falling within a well‐defined fitness window, thus expanding the adaptability potential of the protein.

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The potential of at-home prediction of the formation of urolithiasis by simple multi-frequency electrical conductivity of the urine and the comparison of its performance with urine ion-related indices, color and specific gravity

et al. 2015

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It is important to control daily diet, water intake and life style as well as monitor the quality of urine for urolithiasis prevention. For decades, many ion-related indices have been developed for predicting the formation of urinary stones or urolithiasis, such as EQUILs, relative supersaturation (RSS), Tiselius indices (TI), Robertson risk factor algorithms (RRFA) and more recently, the Bonn risk index. However, they mostly demand robust laboratory analysis, are work-intensive, and even require complex computational programs to get the concentration patterns of several urine analytes. A simple and fast platform for measuring multi-frequency electrical conductivity (MFEC) of morning spot urine (random urine) to predict the onset of urolithiasis was implemented in this study. The performance thereof was compared to ion-related indices, urine color and specific gravity. The concentrations of relevant ions, color, specific gravity (SG) and MFEC (MFEC tested at 1, 10, 100, 5001 KHz and 1 MHz) of 80 random urine samples were examined after collection. Then, the urine samples were stored at 4 °C for 24 h to determine whether sedimentation would occur or not. Ion-activity product index of calcium oxalate (AP(CaOx) EQ2) was calculated. The correlation between AP(CaOx) EQ2, urine color, SG and MFEC were analyzed. AP(CaOx) EQ2, urine color and MFEC (at 5 frequencies) all demonstrated good prediction (p = 0.01, 0.01, 0.01, respectively) for stone formation. The positive correlation between AP(CaOx) EQ2 and MFEC is also significant (p = 0.01). MFEC provides a good metric for predicting the onset of urolithiasis, which is comparable to conventional ion-related indices and urine color. This technology can be implemented with much ease for objectively monitoring the quality of urine at points-of-care or at home.

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Variability in Kidney Stone Incidence Between Black and White South Africans: AGT Pro11Leu Polymorphism Is Not a Factor

Abstract: Our data imply that the AGT Pro11Leu polymorphism is not directly responsible for the low incidence of stone formation in B. We conclude that other factors must be instrumental in protecting the B population from urolithiasis.

Cited by 5 publications

References 25 publications

Effects of alanine:glyoxylate aminotransferase variants and pyridoxine sensitivity on oxalate metabolism in a cell-based cytotoxicity assay

Effects of alanine:glyoxylate aminotransferase variants and pyridoxine sensitivity on oxalate metabolism in a cell-based cytotoxicity assay

Structural dynamics shape the fitness window of alanine:glyoxylate aminotransferase

The potential of at-home prediction of the formation of urolithiasis by simple multi-frequency electrical conductivity of the urine and the comparison of its performance with urine ion-related indices, color and specific gravity

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