Kidney Week

Abstract: TH-PO0009

Identification of Novel Damaging Variants in the Oxalate Transporter SLC26A6 Associated with Kidney Stone Disease

Session Information

• Mineral Balance: Physiology and Pathophysiology
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Bizer, Benjamin, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Benjamin Bizer, MD

• Borisov, Oleg, Universitatsklinikum Freiburg, Freiburg, BW, Germany

Oleg Borisov, PhD

• Penter, Tiberius Carl Friedrich, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Tiberius Carl Friedrich Penter

• Pitzken, Felix, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Felix Pitzken

• Song, Esther Gawon, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Esther Gawon Song

• Chang, Minhwang, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Minhwang Chang, MS, PhD

• Lieske, John C., Mayo Clinic Minnesota, Rochester, Minnesota, United States

John C. Lieske, MD, FASN

• Romero, Michael F., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Michael F. Romero, PhD

• Aronson, Peter S., Yale School of Medicine, New Haven, Connecticut, United States

Peter S. Aronson, MD, FASN

• Kottgen, Anna, Universitatsklinikum Freiburg, Freiburg, BW, Germany

Anna Kottgen, MD, MPH

• Knauf, Felix, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Felix Knauf, MD

Background

Calcium oxalate nephrolithiasis is the most common form of kidney stone disease. SLC26A6 is an oxalate transporter whose deletion in mice can cause hyperoxaluria and spontaneous calcium oxalate stone formation. However, evidence for a pathogenic role of human SLC26A6 variants remains limited. This study aims to address this knowledge gap.

Methods

SLC26A6 variants were identified in the UK Biobank 470,000-participant whole-exome sequencing dataset and annotated using the Ensembl Variant Effect Predictor. Qualifying variants (non-synonymous variants with gnomAD global MAF = 0% and REVEL score ≥0.25, and UK Biobank alternative allele frequency <0.005%) were aggregated into an ultra-rare damaging collapsing mask. Selected variants were cloned into Xenopus expression vectors and expressed in Xenopus laevis oocytes, with ¹⁴C- oxalate uptake as the functional readout.

Results

Gene-based collapsing testing revealed enrichment of ultra-rare damaging SLC26A6 variants in kidney stone cases (10/4,302; 0.23%) compared to controls (265/198,403; 0.13%; OR 2.53, p = 0.035). Two previously uncharacterized SLC26A6 variants (p.T219P and p.L686P, ENST00000395550) showed significantly reduced oxalate transport in functional assays, with reductions of 80% and 60% compared to wild-type, respectively (Figure 1).

Conclusion

These findings provide integrated human genetic and functional evidence supporting an association between rare deleterious SLC26A6 variants and kidney stones. The impaired oxalate transport observed for selected variants suggests a role in disease pathogenesis. Further studies are needed to determine SLC26A6 structural changes and how these variants may disrupt systemic oxalate homeostasis increasing human kidney stone risk.

Figure 1. Oxalate transport in WT and mutants. Data shown as individual points with mean ± SD; p values from ANOVA with Bonferroni correction compared to WT.