Mutations in SLC26A1 Cause Nephrolithiasis

Am J Hum Genet. 2016 Jun 2;98(6):1228-1234. doi: 10.1016/j.ajhg.2016.03.026. Epub 2016 May 19.


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.

MeSH terms

  • Amino Acid Sequence
  • Anion Transport Proteins / chemistry
  • Anion Transport Proteins / genetics*
  • Anion Transport Proteins / metabolism*
  • Bicarbonates / metabolism
  • Fluorescent Antibody Technique
  • Glycosylation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoblotting
  • Mutation / genetics*
  • Nephrolithiasis / etiology*
  • Nephrolithiasis / pathology
  • Protein Conformation
  • Protein Folding
  • Protein Transport
  • Real-Time Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Sulfate Transporters
  • Sulfates / metabolism


  • Anion Transport Proteins
  • Bicarbonates
  • SLC26A1 protein, human
  • Sulfate Transporters
  • Sulfates