Human liver peroxisomal alanine:glyoxylate aminotransferase: Different stability under chemical stress of the major allele, the minor allele, and its pathogenic G170R variant

Cellini, Barbara; Lorenzetto, Antonio; Montioli, Riccardo; Oppici, Elisa; Voltattorni, Carla Borri

doi:10.1016/j.biochi.2010.08.005

Cited by 53 publications

(71 citation statements)

References 25 publications

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“…We next analyzed alleles of AGT associated with PH1, including a minor allele polymorphic variant (AGTmi, with amino acid substitutions P11L and I340M), and a disease variant associated with the minor allele, I244T (AGTmi I244T ). AGTmi has a mild destabilizing effect, while the AGTmi I244T disease variant has greatly reduced stability (Lumb and Danpure 2000;Hopper et al 2008;Cellini et al 2010a). Using IDESA, we observed robust differences in growth of yeast expressing these variants, with yeast expressing AGTmi and AGTmi I244T showing poorer growth than yeast expressing wild-type AGT and yeast expressing AGTmi I244T showing a temperature-sensitive phenotype at 37° (Figure 1, B and C).…”

Section: Analysis Of Disease Variants Using Idesamentioning

confidence: 89%

Rapid Profiling of Disease Alleles Using a Tunable Reporter of Protein Misfolding

et al. 2012

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Many human diseases are caused by genetic mutations that decrease protein stability. Such mutations may not specifically affect an active site, but can alter protein folding, abundance, or localization. Here we describe a high-throughput cell-based stability assay, IDESA (intra-DHFR enzyme stability assay), where stability is coupled to cell proliferation in the model yeast, Saccharomyces cerevisiae. The assay requires no prior knowledge of a protein's structure or activity, allowing the assessment of stability of proteins that have unknown or difficult to characterize activities, and we demonstrate use with a range of disease-relevant targets, including human alanine:glyoxylate aminotransferase (AGT), superoxide dismutase (SOD-1), DJ-1, p53, and SMN1. The assay can be carried out on hundreds of disease alleles in parallel or used to identify stabilizing small molecules (pharmacological chaperones) for unstable alleles. As demonstration of the general utility of this assay, we analyze stability of disease alleles of AGT, deficiency of which results in the kidney stone disease, primary hyperoxaluria type I, identifying mutations that specifically affect the protein-active site chemistry.

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Section: Analysis Of Disease Variants Using Idesamentioning

confidence: 89%

Rapid Profiling of Disease Alleles Using a Tunable Reporter of Protein Misfolding

et al. 2012

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“…The exact role of the G170R mutation was unclear as it had relatively little effect on the conformation and other properties of AGT on its own (8,18,20,33). However, it did appear to interact synergistically with the P11L polymorphism to interfere with AGT dimerization and possibly freeing up the otherwise trapped N-terminal extension (8,9).…”

Section: Discussionmentioning

confidence: 99%

Four of the Most Common Mutations in Primary Hyperoxaluria Type 1 Unmask the Cryptic Mitochondrial Targeting Sequence of Alanine:glyoxylate Aminotransferase Encoded by the Polymorphic Minor Allele

Fargue

Lewin

Rumsby

et al. 2013

Journal of Biological Chemistry

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Background:The hereditary kidney stone disease primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). Results: Four mutations interact with a common polymorphism resulting in AGT mitochondrial mistargeting. Conclusion:The synergy between the polymorphism and mutations in AGT is more common than thought previously. Significance: This has implications for the design of chemotherapeutic agents.

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“…[19][20][21][22][23][24] AGXT p.G170R is associated with mistargeting of the AGT homodimer to mitochondria and the associated unmasking of the p.P11L mitochondrial targeting sequence (MTS) of the "minor" p.P11L/p.I340M haplotype. [25][26][27][28][29] Patients with p.G170R have milder renal disease and respond to pyridoxine treatment, a cofactor that reduces enzyme mistargeting. 25,27,28,[30][31][32] The mutations p.G41R, p.F152I and p.I244T also unmask the MTS if present on the minor allele, and anecdotal evidence suggests that patients with p.F152I benefit from pyridoxine treatment.…”

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confidence: 99%

“…[25][26][27][28][29] Patients with p.G170R have milder renal disease and respond to pyridoxine treatment, a cofactor that reduces enzyme mistargeting. 25,27,28,[30][31][32] The mutations p.G41R, p.F152I and p.I244T also unmask the MTS if present on the minor allele, and anecdotal evidence suggests that patients with p.F152I benefit from pyridoxine treatment. 29,30,32,33 Detecting genotype-phenotype correlations beyond the minor allele requiring (MiR) variants is complicated by the allelic heterogeneity and marked phenotypic variability, both intrafamilial and among unrelated patients with the same allelic combination, suggesting environmental and modifier gene roles.…”

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Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

Hopp

Cogal

Bergstralh³

et al. 2015

Journal of the American Society of Nephrology

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Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.

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Human liver peroxisomal alanine:glyoxylate aminotransferase: Different stability under chemical stress of the major allele, the minor allele, and its pathogenic G170R variant

Cited by 53 publications

References 25 publications

Rapid Profiling of Disease Alleles Using a Tunable Reporter of Protein Misfolding

Rapid Profiling of Disease Alleles Using a Tunable Reporter of Protein Misfolding

Four of the Most Common Mutations in Primary Hyperoxaluria Type 1 Unmask the Cryptic Mitochondrial Targeting Sequence of Alanine:glyoxylate Aminotransferase Encoded by the Polymorphic Minor Allele

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

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