Abstract: FR-PO597
A Rare Cause of Proteinuria and Nephrolithiasis: Biallelic SLC26A1 Variants
Session Information
- Genetic Diseases: Tubulopathies
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Elhassan, Elhussein Aamir Elzein, Royal College of Surgeons in Ireland, Dublin, Ireland
- Long, Eva B., University College Cork, Cork, Cork, Ireland
- Benson, Katherine A., Royal College of Surgeons in Ireland, Dublin, Dublin, Ireland
- Cavalleri, Gianpiero, Royal College of Surgeons in Ireland, Dublin, Dublin, Ireland
- Conlon, Peter J., Beaumont Hospital, Dublin, Ireland
Introduction
Up to 2% of adult nephrolithiasis cases are attributable to a monogenic disease, a clinically and genetically heterogeneous group. Although high-throughput sequencing has identified >90 nephrolithiasis-causing genes, some of these genes are understudied.
Case Description
This Irish family consists of 2 affected siblings. The proband (W94_1), a 63-year-old woman, presented with recurrent non-obstructive nephrolithiasis, urinary infections, and proteinuria. Sonography revealed normal-sized kidneys. In addition, she reported bilateral sensorineural deafness since childhood, indicating hearing aids at age 50 years. No further evidence of systemic involvement was identified. At the last follow-up, aged 63 years, she exhibited reduced estimated glomerular filtration rate (eGFR). Despite recurrent nephrolithiasis, the kidney function of her 61-year-old brother (W94_2) is adequate (eGFR = 88 mL/min). At the time of genetic analysis, oxalate and calcium excretion in the urine were normal, with normal serum bicarbonate.
Genetic testing revealed both harbor biallelic variants in The Solute Carrier Family 26-Member 1 (SLC26A1) gene (NM_022042:c.C1073T; p.S358L and c.C554T; p.T185M) associated with monogenic calcium oxalate nephrolithiasis. The SLC26A1 gene encodes for an anion transporter critical in oxalate and sulfate hemostasis. These reported SLC26A1 variants (p.S358L and p.T185M) occurred at conserved resides and reported at a low frequency in population databases, such as the Genome Aggregation Database (gnomAD). It is localized into the basolateral membrane of proximal tubules. Functional studies of similar reported variants demonstrate a dysfunctional process of protein and impaired transporter activity. However, the effect of SLC26A1 on oxalate homeostasis, which causes hyperoxaluria and urolithiasis, remains controversial. Nevertheless, its role in sulfate homeostasis in humans has only recently been established.
Discussion
Clinical features of kidney stone formers harboring SLC26A1 variants can vary, indicating the potential expressivity. Awareness of monogenic nephrolithiasis, especially in families with history, should allow early diagnosis, treatment, and personalized counseling.