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.
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 either 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 non-Ashkenazi 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 non-Ashkenazi study group. No correlation was detected between hyperoxaluria and HOGA1 variants.
This study shows that mutations in HOGA1 do not confer a dominant phenotype in the form of calcium-oxalate kidney stone disease or hyperoxaluria.
The Journal of urology. 2020 Dec 22 [Epub ahead of print]
Roi Bar, Efrat Ben-Shalom, Mordechai Duvdevani, Ruth Belostotsky, Martin R Pollak, David B Mount, Ruth Bar-Gal, Ehud Gnessin, Shay Tzur, Gary C Curhan, Yaacov Frishberg
Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel., Department of Urology, Hadassah Hebrew University Hospital, Jerusalem, Israel., Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts., Division of Nephrology, Brigham and Women's Hospital, Boston, Massachusetts., Department of Urology, Shaare Zedek Medical Center, Jerusalem, Israel., Genomic Research Department, Emedgene Technologies, Tel Aviv, Israel.