Mutations in HOGA1 do Not Confer a Dominant Phenotype Manifesting as Kidney Stone Disease.

PURPOSE: The etiology of calcium-oxalate kidney stone formation remains elusive. Biallelic mutations in HOGA1 are responsible for primary hyperoxaluria type 3 and result in oxalate overproduction and kidney stone disease. Our previous study showed that carriers of HOGA1 mutations have elevated urinary levels of oxalate precursors. In this study we explored the possibility that mutations in HOGA1 confer a dominant phenotype in the form of kidney stone disease or hyperoxaluria. MATERIALS AND METHODS: An observational analytic case control study was designed to determine the prevalence of pathogenic HOGA1 mutations among adults with calcium-oxalate kidney stone disease. Given the high prevalence of HOGA1 mutations among Ashkenazi Jews, this group was evaluated separately. Carrier frequency of any of the 52 reported pathogenic mutations was compared to data derived from gnomAD for the corresponding ethnic group. Sanger sequencing of HOGA1 gene was performed on DNA samples from the following groups: 60 Ashkenazi Jews and 86 nonAshkenazi calcium-oxalate stone formers, 150 subjects with low and 150 with high urinary oxalate levels. RESULTS: The carrier prevalence of pathogenic mutations among the Ashkenazi Jews was 1.7% compared to 2.8% in the corresponding control group (p=0.9 OR=0.6 95% CI 0.01-3.51). We did not detect any mutation among the nonAshkenazi study group. No correlation was detected between hyperoxaluria and HOGA1 variants. CONCLUSIONS: This study shows that mutations in HOGA1 do not confer a dominant phenotype in the form of calcium-oxalate kidney stone disease or hyperoxaluria.

Translation inhibition corrects aberrant localization of mutant alanine-glyoxylate aminotransferase: possible therapeutic approach for hyperoxaluria.

Primary hyperoxaluria type 1 is a severe kidney stone disease caused by abnormalities of the peroxisomal alanine-glyoxylate aminotransferase (AGT). The most frequent mutation G170R results in aberrant mitochondrial localization of the active enzyme. To evaluate the population of peroxisome-localized AGT, we developed a quantitative Glow-AGT assay based on the self-assembly split-GFP approach and used it to identify drugs that can correct mislocalization of the mutant protein. In line with previous reports, the Glow-AGT assay showed that mitochondrial transport inhibitors DECA and monensin increased peroxisomal localization of the mutant. Here, we demonstrate that prolonged treatment with the translation elongation inhibitor emetine, a medicinal alkaloid used in treatment of amoebiasis, corrected G170R-AGT mislocalization. Furthermore, emetine reduced the augmented oxalate level in culture media of patient-derived hepatocytes bearing the G170R mutation. A distinct translation inhibitor GC7 had a similar effect on the mutant Glow-AGT relocalization indicating that mild translation inhibition is a promising therapeutic approach for primary hyperoxaluria type 1 caused by AGT misfolding/mistargeting. KEY MESSAGES: • There is no effective conservative treatment to decrease oxalate production in PH1 patients. • Chemical chaperones rescue mislocalization of mutant AGT and reduce oxalate levels. • We have developed an assay for precise monitoring of the peroxisomal AGT. • Inhibition of translation by emetine reroutes the mutant protein to peroxisome. • Mild translation inhibition is a promising cure for conformational disorders.