Mutations in SLC26A1 Cause Nephrolithiasis

Am J Hum Genet. 2016 Jun 2;98(6):1228-1234. doi: 10.1016/j.ajhg.2016.03.026.

Heon Yung Gee ¹, Ikhyun Jun ², Daniela A Braun ³, Jennifer A Lawson ³, Jan Halbritter ⁴, Shirlee Shril ³, Caleb P Nelson ⁵, Weizhen Tan ³, Deborah Stein ³, Ari J Wassner ⁶, Michael A Ferguson ³, Zoran Gucev ⁷, John A Sayer ⁸, Danko Milosevic ⁹, Michelle Baum ³, Velibor Tasic ⁷, Min Goo Lee ¹⁰, Friedhelm Hildebrandt ¹¹

Affiliations

1 Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2 Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; The Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul 03722, Korea.
3 Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
4 Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Endocrinology and Nephrology, Department of Internal Medicine, University Clinic Leipzig, Leipzig 04103, Germany.
5 Divisions of Urology and General Pediatrics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
6 Division of Endocrinology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
7 Medical Faculty Skopje, University Children's Hospital, Skopje 1000, Macedonia.
8 Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
9 Department of Pediatric Nephrology, Dialysis, and Transplantation, Clinical Hospital Center Zagreb, University of Zagreb Medical School, Zagreb 10000, Croatia.
10 Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address: [email protected].
11 Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

PMID: 27210743 DOI: 10.1016/j.ajhg.2016.03.026

Abstract

Nephrolithiasis, a condition in which urinary supersaturation leads to stone formation in the urinary system, affects about 5%-10% of individuals worldwide at some point in their lifetime and results in significant medical costs and morbidity. To date, mutations in more than 30 genes have been described as being associated with nephrolithiasis, and these mutations explain about 15% of kidney stone cases, suggesting that additional nephrolithiasis-associated genes remain to be discovered. To identify additional genes whose mutations are linked to nephrolithiasis, we performed targeted next-generation sequencing of 18 hypothesized candidate genes in 348 unrelated individuals with kidney stones. We detected biallelic mutations in SLC26A1 (solute carrier family 26 member 1) in two unrelated individuals with calcium oxalate kidney stones. We show by immunofluorescence, immunoblotting, and glycosylation analysis that the variant protein mimicking p.Thr185Met has defects in protein folding or trafficking. In addition, by measuring anion exchange activity of SLC26A1, we demonstrate that all the identified mutations in SLC26A1 result in decreased transporter activity. Our data identify SLC26A1 mutations as causing a recessive Mendelian form of nephrolithiasis.

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