SLC26A1 is a major determinant of sulfate homeostasis in humans
Anja Pfau, … , Thomas J. Jentsch, Felix Knauf
Anja Pfau, … , Thomas J. Jentsch, Felix Knauf
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e161849. https://doi.org/10.1172/JCI161849.
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Research Article Genetics Nephrology

SLC26A1 is a major determinant of sulfate homeostasis in humans

Abstract

Sulfate plays a pivotal role in numerous physiological processes in the human body, including bone and cartilage health. A role of the anion transporter SLC26A1 (Sat1) for sulfate reabsorption in the kidney is supported by the observation of hyposulfatemia and hypersulfaturia in Slc26a1-knockout mice. The impact of SLC26A1 on sulfate homeostasis in humans remains to be defined. By combining clinical genetics, functional expression assays, and population exome analysis, we identify SLC26A1 as a sulfate transporter in humans and experimentally validate several loss-of-function alleles. Whole-exome sequencing from a patient presenting with painful perichondritis, hyposulfatemia, and renal sulfate wasting revealed a homozygous mutation in SLC26A1, which has not been previously described to the best of our knowledge. Whole-exome data analysis of more than 5,000 individuals confirmed that rare, putatively damaging SCL26A1 variants were significantly associated with lower plasma sulfate at the population level. Functional expression assays confirmed a substantial reduction in sulfate transport for the SLC26A1 mutation of our patient, which we consider to be novel, as well as for the additional variants detected in the population study. In conclusion, combined evidence from 3 complementary approaches supports SLC26A1 activity as a major determinant of sulfate homeostasis in humans. In view of recent evidence linking sulfate homeostasis with back pain and intervertebral disc disorder, our study identifies SLC26A1 as a potential target for modulation of musculoskeletal health.

Authors

Anja Pfau, Karen I. López-Cayuqueo, Nora Scherer, Matthias Wuttke, Annekatrin Wernstedt, Daniela González Fassrainer, Desiree E.C. Smith, Jiddeke M. van de Kamp, Katharina Ziegeler, Kai-Uwe Eckardt, Friedrich C. Luft, Peter S. Aronson, Anna Köttgen, Thomas J. Jentsch, Felix Knauf

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Figure 1

MRI demonstrated perichondritis at the level of the third and fourth ribs.

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MRI demonstrated perichondritis at the level of the third and fourth rib...
Axial fat-saturated T1-weighted images after administration of intravenous contrast agent (gadolinium): Linear contrast enhancement of the costal cartilage on both sides at the level of the third and fourth ribs (white arrowheads), predominantly at the costochondral junction, consistent with perichondritis. Note also the subtle diffuse enhancement of the adjacent soft tissue on the right side.