Mutations in SLC26A1 Cause Nephrolithiasis

Heon Yung Gee; Ikhyun Jun; Daniela A. Braun; Jennifer A. Lawson; Jan Halbritter; Shirlee Shril; Caleb P. Nelson; Weizhen Tan; Deborah Stein; Ari J. Wassner; Michael A. Ferguson; Zoran Gucev; John A. Sayer; Danko Milosevic; Michelle Baum; Velibor Tasic; Min Goo Lee; Friedhelm Hildebrandt

doi:10.1016/j.ajhg.2016.03.026

Mutations in SLC26A1 Cause Nephrolithiasis

Heon Yung Gee, Ikhyun Jun, Daniela A. Braun, Jennifer A. Lawson, Jan Halbritter, Shirlee Shril, Caleb P. Nelson, Weizhen Tan, Deborah Stein, Ari J. Wassner, Michael A. Ferguson, Zoran Gucev, John A. Sayer, Danko Milosevic, Michelle Baum, Velibor Tasic, Min Goo Lee, Friedhelm Hildebrandt

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1228-1234
Number of pages	7
Journal	American Journal of Human Genetics
Volume	98
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2016.03.026
Publication status	Published - 2016 Jun 2

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2016 American Society of Human Genetics.

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2016.03.026

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Gee, H. Y., Jun, I., Braun, D. A., Lawson, J. A., Halbritter, J., Shril, S., Nelson, C. P., Tan, W., Stein, D., Wassner, A. J., Ferguson, M. A., Gucev, Z., Sayer, J. A., Milosevic, D., Baum, M., Tasic, V., Lee, M. G., & Hildebrandt, F. (2016). Mutations in SLC26A1 Cause Nephrolithiasis. American Journal of Human Genetics, 98(6), 1228-1234. https://doi.org/10.1016/j.ajhg.2016.03.026

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title = "Mutations in SLC26A1 Cause Nephrolithiasis",

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.",

author = "Gee, {Heon Yung} and Ikhyun Jun and Braun, {Daniela A.} and Lawson, {Jennifer A.} and Jan Halbritter and Shirlee Shril and Nelson, {Caleb P.} and Weizhen Tan and Deborah Stein and Wassner, {Ari J.} and Ferguson, {Michael A.} and Zoran Gucev and Sayer, {John A.} and Danko Milosevic and Michelle Baum and Velibor Tasic and Lee, {Min Goo} and Friedhelm Hildebrandt",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2016 American Society of Human Genetics.",

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AU - Gee, Heon Yung

AU - Jun, Ikhyun

AU - Braun, Daniela A.

AU - Lawson, Jennifer A.

AU - Halbritter, Jan

AU - Shril, Shirlee

AU - Nelson, Caleb P.

AU - Tan, Weizhen

AU - Stein, Deborah

AU - Wassner, Ari J.

AU - Ferguson, Michael A.

AU - Gucev, Zoran

AU - Sayer, John A.

AU - Milosevic, Danko

AU - Baum, Michelle

AU - Tasic, Velibor

AU - Lee, Min Goo

AU - Hildebrandt, Friedhelm

N1 - Funding Information: 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. Publisher Copyright: © 2016 American Society of Human Genetics.

PY - 2016/6/2

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N2 - 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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Mutations in SLC26A1 Cause Nephrolithiasis

Abstract

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