Mutations in <i>HOGA1</i> do Not Confer a Dominant Phenotype Manifesting as Kidney Stone Disease.

Abstract

The etiology of calcium-oxalate kidney stone formation remains elusive. Biallelic mutations in <i>HOGA1</i> are responsible for primary hyperoxaluria type 3 and result in oxalate overproduction and kidney stone disease. Our previous study showed that carriers of <i>HOGA1</i> mutations have elevated urinary levels of oxalate precursors. In this study we explored the possibility that mutations in <i>HOGA1</i> confer a dominant phenotype in the form of kidney stone disease or hyperoxaluria. An observational analytic case control study was designed to determine the prevalence of pathogenic <i>HOGA1</i> mutations among adults with calcium-oxalate kidney stone disease. Given the high prevalence of <i>HOGA1</i> 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 <i>HOGA1</i> 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. 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 <i>HOGA1</i> variants. This study shows that mutations in <i>HOGA1</i> do not confer a dominant phenotype in the form of calcium-oxalate kidney stone disease or hyperoxaluria.