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SLC26A1 is a major determinant of sulfate homeostasis in humans

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 mic...

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Autores principales: Pfau, Anja, López-Cayuqueo, Karen I., Scherer, Nora, Wuttke, Matthias, Wernstedt, Annekatrin, González Fassrainer, Daniela, Smith, Desiree E.C., van de Kamp, Jiddeke M., Ziegeler, Katharina, Eckardt, Kai-Uwe, Luft, Friedrich C., Aronson, Peter S., Köttgen, Anna, Jentsch, Thomas J., Knauf, Felix
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9888379/
https://www.ncbi.nlm.nih.gov/pubmed/36719378
http://dx.doi.org/10.1172/JCI161849
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author Pfau, Anja
López-Cayuqueo, Karen I.
Scherer, Nora
Wuttke, Matthias
Wernstedt, Annekatrin
González Fassrainer, Daniela
Smith, Desiree E.C.
van de Kamp, Jiddeke M.
Ziegeler, Katharina
Eckardt, Kai-Uwe
Luft, Friedrich C.
Aronson, Peter S.
Köttgen, Anna
Jentsch, Thomas J.
Knauf, Felix
author_facet Pfau, Anja
López-Cayuqueo, Karen I.
Scherer, Nora
Wuttke, Matthias
Wernstedt, Annekatrin
González Fassrainer, Daniela
Smith, Desiree E.C.
van de Kamp, Jiddeke M.
Ziegeler, Katharina
Eckardt, Kai-Uwe
Luft, Friedrich C.
Aronson, Peter S.
Köttgen, Anna
Jentsch, Thomas J.
Knauf, Felix
author_sort Pfau, Anja
collection PubMed
description 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.
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spelling pubmed-98883792023-02-06 SLC26A1 is a major determinant of sulfate homeostasis in humans Pfau, Anja López-Cayuqueo, Karen I. Scherer, Nora Wuttke, Matthias Wernstedt, Annekatrin González Fassrainer, Daniela Smith, Desiree E.C. van de Kamp, Jiddeke M. Ziegeler, Katharina Eckardt, Kai-Uwe Luft, Friedrich C. Aronson, Peter S. Köttgen, Anna Jentsch, Thomas J. Knauf, Felix J Clin Invest Research Article 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. American Society for Clinical Investigation 2023-02-01 /pmc/articles/PMC9888379/ /pubmed/36719378 http://dx.doi.org/10.1172/JCI161849 Text en © 2023 Pfau et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Pfau, Anja
López-Cayuqueo, Karen I.
Scherer, Nora
Wuttke, Matthias
Wernstedt, Annekatrin
González Fassrainer, Daniela
Smith, Desiree E.C.
van de Kamp, Jiddeke M.
Ziegeler, Katharina
Eckardt, Kai-Uwe
Luft, Friedrich C.
Aronson, Peter S.
Köttgen, Anna
Jentsch, Thomas J.
Knauf, Felix
SLC26A1 is a major determinant of sulfate homeostasis in humans
title SLC26A1 is a major determinant of sulfate homeostasis in humans
title_full SLC26A1 is a major determinant of sulfate homeostasis in humans
title_fullStr SLC26A1 is a major determinant of sulfate homeostasis in humans
title_full_unstemmed SLC26A1 is a major determinant of sulfate homeostasis in humans
title_short SLC26A1 is a major determinant of sulfate homeostasis in humans
title_sort slc26a1 is a major determinant of sulfate homeostasis in humans
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9888379/
https://www.ncbi.nlm.nih.gov/pubmed/36719378
http://dx.doi.org/10.1172/JCI161849
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