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.
authors.affiliation: 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.
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: 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.
authors.forename: Ikhyun
authors.initials: I
authors.lastname: Jun
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Braun
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lawson
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shirlee
authors.initials: S
authors.lastname: Shril
authors.affiliation: Divisions of Urology and General Pediatrics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Caleb P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Tan
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stein
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Wassner
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ferguson
authors.affiliation: Medical Faculty Skopje, University Children's Hospital, Skopje 1000, Macedonia.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gucev
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.affiliation: Department of Pediatric Nephrology, Dialysis, and Transplantation, Clinical Hospital Center Zagreb, University of Zagreb Medical School, Zagreb 10000, Croatia.
authors.forename: Danko
authors.initials: D
authors.lastname: Milosevic
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Baum
authors.affiliation: Medical Faculty Skopje, University Children's Hospital, Skopje 1000, Macedonia.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address: mlee@yuhs.ac.
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000595:Amino Acid Sequence; D027321:Anion Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015151:Immunoblotting; D009154:Mutation / Q000235:genetics*; D053040:Nephrolithiasis / Q000209:etiology* / Q000473:pathology; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport; D060888:Real-Time Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D000076988:Sulfate Transporters; D013431:Sulfates / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D001639:Bicarbonates; C473560:SLC26A1 protein, human; D000076988:Sulfate Transporters; D013431:Sulfates