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

Abstract

Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10−8) and 27.3% (P = 6.9 × 10−14) decrease in serum sulfate, respectively (P = 8.8 × 10-20 for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10−12). Consistent with sulfate’s role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1. This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.

Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis

“…SLC13A1 nonsense variants cause decreased serum sulfate, likely due to decreased sulfate (re)absorption in the intestines and kidneys [17] . However the mechanism by which these variants result in decreased serum DHEA is not as clear.…”

“…We previously reported on two rare, non-linked, nonsense variants in SLC13A1 (rs28364172, c.34C > T, p.R12X and rs138275989, c.144G > A, p.W48X) that are enriched in frequency in the Old Order Amish (Amish) population (1.2-fold (0.29% vs. 0.23%) and 3.7-fold (0.74% vs. 0.20%), respectively, compared to ESP (EA) allele frequencies) and associated with hyposulfatemia ( P = 9 × 10 − 20 ) [17] . SLC13A1 encodes the apical membrane, sodium-sulfate cotransporter NaS1, which is responsible for sulfate (re)absorption in the intestines and kidneys [18] .…”

“…SLC13A1 encodes the apical membrane, sodium-sulfate cotransporter NaS1, which is responsible for sulfate (re)absorption in the intestines and kidneys [18] . As a result, loss-of-function alleles in this gene cause in decreased serum sulfate levels [17] , [20] , [21] , [22] . The enrichment of these SLC13A1 nonsense variants in the Amish provides us the unique opportunity to dissect the role of sulfate and these sulfate-lowering variants in androgenic hormone homeostasis.…”

Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

“…NaS1, product of the SLC13A1 gene, mediates the absorption of sulfate, an essential micronutrient required for various physiological processes, in the small intestine and its reabsorption in the kidney, thereby regulating sulfate plasma level and sulfate homeostasis (Markovich, 2001;Markovich and Murer, 2004). The two single-nucleotide variants, rs28364172 and rs138275989, were shown to be strongly associated with low serum sulfate level, a so-called hyposulfatemia, as well as the high serum level of the liver transaminases alanine aminotransferase and aspartate aminotransferase (Tise et al, 2016). A potentially detrimental effect of disturbed sulfate homeostasis on liver metabolism is supported by the hyposulfatemic Slc13a1 knockout mouse model showing altered hepatic gene expression associated with increased hepatic lipid, serum cholesterol, and low-density lipoprotein concentration, as well as reduced hepatic glycogen content (Dawson et al, 2006).…”

Structure, organization and tissue expression of the pig SLC13A1 and SLC13A4 sulfate transporter genes

“…Both genes are highly conserved (>80% identity) and have similar tissue expression patterns in mice and humans [16] , [17] . In addition, loss-of-function mutations in human SLC13A1 lead to renal sulfate wasting and reduced plasma sulfate levels [18] , [19] , as found in the Slc13a1 null mouse [13] . Over the past decade, several studies on the Slc13a1 and Slc13a4 null mice have provided valuable insights into the roles of these genes, particularly their obligate requirement for supplying sulfate from mother to fetus [13] , [14] , [15] .…”