ArticleThe Journal of biological chemistry2013
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.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed.
- Impact of Ser81 phosphorylation on alanine: glyoxylate aminotransferase associated with Primary hyperoxaluria type I.Molecular biomedicine · 2026Article
- Genetic Correction of the Most Common Mutation Causing Primary Hyperoxaluria Restores Enzyme Localization and Oxalate Metabolism.Journal of inherited metabolic disease · 2026Article
- A Minor Haplotype Variant Determines the Pathogenicity of the p.Ile279Thr Substitution in the Primary Hyperoxaluria Type 1 Gene, AGXT.Journal of inherited metabolic disease · 2025Article
- Effect of the allelic background on the phenotype of primary hyperoxaluria type I.Current opinion in nephrology and hypertension · 2025Review
- Monogenic features of urolithiasis: A comprehensive review.Asian journal of urology · 2024Review
- Leader peptide or pro-segment mutants of renin are misrouted to mitochondria in autosomal dominant tubulointerstitial kidney disease.Disease models & mechanisms · 2023Article
- Transcriptomic Modulation Reveals the Specific Cellular Response in Chinese Sea Bass (International journal of molecular sciences · 2023Article
- Identification of Human Alanine-Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1.Journal of medicinal chemistry · 2022Article
- Review
- The genetics of kidney stone disease and nephrocalcinosis.Nature reviews. Nephrology · 2022Review
- New Insights Regarding Organ Transplantation in Primary Hyperoxaluria Type 1.Kidney international reports · 2022Article
- Novel therapeutic approaches for the primary hyperoxalurias.Pediatric nephrology (Berlin, Germany) · 2021Review
- Dimerization Drives Proper Folding of Human Alanine:Glyoxylate Aminotransferase But Is Dispensable for Peroxisomal Targeting.Journal of personalized medicine · 2021Article
- Pyridoxine Responsiveness in a Type 1 Primary Hyperoxaluria Patient With a Rare (Atypical)Kidney international reports · 2020Article
- Disease-Associated Genetic Variation in Human Mitochondrial Protein Import.American journal of human genetics · 2019Review
- Two NovelFrontiers in pharmacology · 2019Article
- Review
- Efficacy of Hydroxy-L-proline (HYP) analogs in the treatment of primary hyperoxaluria in Drosophila Melanogaster.BMC nephrology · 2018Article
- Translation inhibition corrects aberrant localization of mutant alanine-glyoxylate aminotransferase: possible therapeutic approach for hyperoxaluria.Journal of molecular medicine (Berlin, Germany) · 2018Article
- Correlation between the molecular effects of mutations at the dimer interface of alanine-glyoxylate aminotransferase leading to primary hyperoxaluria type I and the cellular response to vitamin BJournal of inherited metabolic disease · 2018Article
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Abstract
The gene encoding the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT, EC. 2.6.1.44) exists as two common polymorphic variants termed the "major" and "minor" alleles. The P11L amino acid replacement encoded by the minor allele creates a hidden N-terminal mitochondrial targeting sequence, the unmasking of which occurs in the hereditary calcium oxalate kidney stone disease primary hyperoxaluria type 1 (PH1). This unmasking is due to the additional presence of a common disease-specific G170R mutation, which is encoded by about one third of PH1 alleles. The P11L and G170R replacements interact synergistically to reroute AGT to the mitochondria where it cannot fulfill its metabolic role (i.e. glyoxylate detoxification) effectively. In the present study, we have reinvestigated the consequences of the interaction between P11L and G170R in stably transformed CHO cells and have studied for the first time whether a similar synergism exists between P11L and three other mutations that segregate with the minor allele (i.e. I244T, F152I, and G41R). Our investigations show that the latter three mutants are all able to unmask the cryptic P11L-generated mitochondrial targeting sequence and, as a result, all are mistargeted to the mitochondria. However, whereas the G170R, I244T, and F152I mutants are able to form dimers and are catalytically active, the G41R mutant aggregates and is inactive. These studies open up the possibility that all PH1 mutations, which segregate with the minor allele, might also lead to the peroxisome-to-mitochondrion mistargeting of AGT, a suggestion that has important implications for the development of treatment strategies for PH1.
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