Human SLC26A1 Gene Variants: A Pilot Study

Abstract

Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones.

From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases

“…These findings are consistent with mouse models in which hyposulfatemic, Slc26a1 -knockout mice exhibit nephrocalcinosis and increased calcium oxalate kidney stone formation while hyposulfatemic, Slc13a1 -knockout mice do not exhibit these manifestations ( Dawson et al 2010 ; Markovich 2011a,b , 2012 ). Additionally, SLC26A1 has been suggested to play a role in humans with recurrent calcium oxalate kidney stones ( Dawson et al 2013 ). While the mechanism for nephrocalcinosis, calcium oxalate urolithiasis, and increased serum calcium is not totally clear, these phenotypes associate with decreased Sat1 function, suggesting they may be specific to anion transport rather than sulfate transport.…”

The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man

“…Despite the disruption to oxalate homeostasis and other pathologies exhibited by SAT1-KO mice [19], this gene has not yet been associated with any human disease. However, a recent pilot study examined a small cohort of recurrent, idiopathic calcium oxalate stone formers revealing a number of sequence variants in the SAT1 gene that may be of significance [60]. …”

Extracellular Cl− regulates human SO4 2−/anion exchanger SLC26A1 by altering pH sensitivity of anion transport

“…The rare heterozygous SLC26A1 variant SLC26A1 M132T was found in trans with the homozygous common variant Q566R in a patient with severe nephrocalcinosis requiring nephrectomy [19]. Since residue M132 is highly conserved across species orthologs, and the M132T-encoding variant is absent from dbSNP and predicted to be pathogenic, we subjected SLC26A1 M132T to functional testing in Xenopus oocytes, in isolation and in cis with common variant Q556R.…”

“…The rare heterozygous SLC26A1 variant M132T and the common homozygous variant Q556R, found together in a patient with recurrent nephrolithiasis and nephrocalcinosis [19], did not alter transport of SO 4 2− or oxalate, whether expressed individually or co-expressed (Fig. 13).…”