Abstract: SA-PO0158
Broadening the Phenotypic Spectrum of SLC34A3: A First Report of Autosomal Dominant CKD
Session Information
- Tubular, Metabolic, and Systemic Noncystic Genetic Kidney Diseases
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Razak, Bibi, Washington University in St Louis, St. Louis, Missouri, United States
- Tang, Hoang-Anh Minh, Washington University in St Louis, St. Louis, Missouri, United States
- Chen, Ying Maggie, Washington University in St Louis, St. Louis, Missouri, United States
Introduction
Genetic etiologies underlie approximately 10% of chronic kidney disease (CKD) cases. SLC34A3 encodes the sodium-dependent phosphate cotransporter 2c (NPT2c), which is localized to the apical brush border of the renal proximal tubule, and is essential for maintaining phosphate homeostasis. While mutations in this gene are known to cause mineral imbalances, the role of SLC34A3 in CKD development remains poorly defined.
Case Description
We present a case of a 49-year-old Caucasian female with stage 3 CKD of unknown etiology. She had no history of hypertension or diabetes. Notably, her family history is significant for nephrolithiasis in both her father and son. An initial CKD work up was unremarkable, featuring a bland urine analysis without proteinuria or hematuria and a normal renal ultrasound; specifically negative for nephrocalcinosis or nephrolithiasis. Due to the cryptogenic nature of her renal impairment, she underwent genetic testing, which identified a heterozygous pathogenic mutation in SLC34A3 (p. S192L).
Biallelic mutations in SLC34A3 cause Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH), a rare autosomal recessive disorder, while heterozygous carriers face an increased risk of nephrolithiasis and nephrocalcinosis. Although CKD in these patients is typically attributed to chronic mineral deposition, our patient's renal ultrasound showed no structural calcifications. This unique presentation strongly suggests that the SLC34A3 p.S192L variant may function as an autosomal dominant driver of CKD.
Discussion
To our knowledge, no existing reports characterize SLC34A3 mutations as a primary CKD driver in the absence of nephrocalcinosis or nephrolithiasis. Our case suggests that the SLC34A3 p.S192L missense variant may result in renal impairment through mechanisms beyond mineral deposition. We hypothesize that this missense mutation may lead to protein misfolding and subsequent endoplasmic reticulum stress within the proximal tubular cells. Such cellular stress could trigger an inflammatory or fibrotic pathway, ultimately leading to CKD. We will utilize patient-derived kidney organoids to validate our hypothesis.
Our case highlights a potential novel disease mechanism, where heterozygous NPT2c defects may induce direct tubular injury independent of stone formation.