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, Sonia; Lewin, Jackie; Rumsby, Gill; Danpure, Christopher J.

doi:10.1074/jbc.m112.432617

Cited by 78 publications

(105 citation statements)

References 49 publications

(85 reference statements)

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“…5 Patients homozygous for one of the four MiR alleles 29 had milder PH1 ( Figure 2, Table 3), as suggested for p.G170R, 25 but separating p.G170R from the other MiR alleles highlighted that later onset of ESRD was associated only with p.G170R (Figure 3); renal survival of the other MiR patients was similar to that of patients with truncating or non-MiR nontruncating alleles. These results emphasize the incompletely penetrant nature/ variable expressivity of p.G170R and suggest a different pathomechanism for other MiR alleles, such as monomer aggregation or active site disruption, as indicated for p.G41R.…”

Section: Discussionmentioning

confidence: 91%

“…These results emphasize the incompletely penetrant nature/ variable expressivity of p.G170R and suggest a different pathomechanism for other MiR alleles, such as monomer aggregation or active site disruption, as indicated for p.G41R. 29,44 This is important in considering pyridoxine therapy for patients with other MiR alleles because this cofactor is thought to stabilize the monomer/dimer. Nevertheless, anecdotal evidence suggests pyridoxine response in a variety of AGXT mutation patients (including p.F152I or two truncating alleles), indicating that alternative therapeutic benefits of pyridoxine may exist (e.g., influence on gene expression and/or enzyme activity).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, although all MiR alleles unmask the functional MTS, their penetrance significantly differs. 29 Allelic Associations with Phenotype in PH2 and PH3 To evaluate genotype-phenotype correlations in our PH2 cohort, patients were grouped according to mutation type (two truncating, two nontruncating, or a truncating plus a nontruncating allele). However, no significant associations were observed with age at symptoms or ESRD, nephrocalcinosis, and urine chemistry (Supplemental Table 3).…”

Section: Genotype-phenotype Comparisons Between Ph Typesmentioning

confidence: 99%

“…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. 5,25 PH2 is generally less severe than PH1 but with a similar age at first symptoms.…”

mentioning

confidence: 99%

“…[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%

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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

209

255

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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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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Genotype-phenotype Comparisons Between Ph Typesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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

209

255

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Insights into the pathogenesis of primary hyperoxaluria type I from the structural dynamics of alanine:glyoxylate aminotransferase variants

Vankova,

Pacheco‐Garcia,

Loginov

et al. 2024

FEBS Letters

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Primary hyperoxaluria type I (PH1) is caused by deficient alanine:glyoxylate aminotransferase (AGT) activity. PH1‐causing mutations in AGT lead to protein mistargeting and aggregation. Here, we use hydrogen‐deuterium exchange (HDX) to characterize the wild‐type (WT), the LM (a polymorphism frequent in PH1 patients) and the LM G170R (the most common mutation in PH1) variants of AGT. We provide the first experimental analysis of AGT structural dynamics, showing that stability is heterogeneous in the native state and providing a blueprint for frustrated regions with potentially functional relevance. The LM and LM G170R variants only show local destabilization. Enzymatic transamination of the pyridoxal 5‐phosphate cofactor bound to AGT hardly affects stability. Our study, thus, supports that AGT misfolding is not caused by dramatic effects on structural dynamics.

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Folding Defects Leading to Primary Hyperoxaluria

Oppici

Dindo

Conter

et al. 2017

Handbook of Experimental Pharmacology

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Protein misfolding is becoming one of the main mechanisms underlying inherited enzymatic deficits. This review is focused on primary hyperoxalurias, a group of disorders of glyoxylate detoxification associated with massive calcium oxalate deposition mainly in the kidneys. The most common and severe form, primary hyperoxaluria Type I, is due to the deficit of liver peroxisomal alanine/glyoxylate aminotransferase (AGT). Various studies performed in the last decade clearly evidence that many pathogenic missense mutations prevent the AGT correct folding, leading to various downstream effects including aggregation, increased degradation or mistargeting to mitochondria. Primary hyperoxaluria Type II and primary hyperoxaluria Type III are due to the deficit of glyoxylate reductase/hydroxypyruvate reductase (GRHPR) and 4-hydroxy-2-oxoglutarate aldolase (HOGA1), respectively. Although the molecular features of pathogenic variants of GRHPR and HOGA1 have not been investigated in detail, the data available suggest that some of them display folding defects. Thus, primary hyperoxalurias can be ranked among protein misfolding disorders, because in most cases the enzymatic deficit is due to the inability of each enzyme to reach its native and functional conformation. It follows that molecules able to improve the folding yield of the enzymes involved in each disease form could represent new therapeutic strategies.

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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

Cited by 78 publications

References 49 publications

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

Insights into the pathogenesis of primary hyperoxaluria type I from the structural dynamics of alanine:glyoxylate aminotransferase variants

Folding Defects Leading to Primary Hyperoxaluria

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