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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We thank the physicians and the participating families for their contributions. We also thank Catherine Matero, Elizabeth Andrews, Brittany Fisher, Leslie Spaneas, and Jennifer Drucker for their help with patient enrollment and clinical information. F.H. is the Warren E. Grupe Professor of Pediatrics. This research was supported by grants DK1069274, DK1068306, and DK064614 (to F.H.) from the NIH, 6-FY11-241 (to F.H.) from the March of Dimes Foundation, 2013R1A3A2042197 (to M.G.L.) and 2015R1D1A1A01056685 (to H. Y. G) from the National Research Foundation of Korea, Ministry of Science, ICT and Future Planning, and 2015-32-0047 (to H.Y.G) from the Yonsei University College of Medicine.
© 2016 American Society of Human Genetics.
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