| Autor: |
Pfau A; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany., López-Cayuqueo KI; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany., Scherer N; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center and.; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany., Wuttke M; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center and., Wernstedt A; SYNLAB MVZ Humane Genetik, Munich, Germany., González Fassrainer D; SYNLAB MVZ Humane Genetik, Munich, Germany., Smith DE; Metabolic Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience and., van de Kamp JM; Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands., Ziegeler K; Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany., Eckardt KU; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Luft FC; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany., Aronson PS; Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA., Köttgen A; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center and.; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany., Jentsch TJ; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.; NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany., Knauf F; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, USA. |
| Abstrakt: |
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. |
