Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia
Purpose: Sulfate is vital for many physiological processes, including the structural and functional maintenance of macromolecules and formation of sulfur-containing compounds essential for cartilage and bone development. SLC13A1 is a sodium-sulfate cotransporter primarily expressed in the kidney, wh...
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Elsevier
2025-01-01
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| Series: | Genetics in Medicine Open |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S294977442401104X |
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| author | Christina G. Tise Katie Ashton Lachlan de Hayr Kun-Di Lee Omkar L. Patkar Emma Krzesinski Jennifer A. Bassetti Erin M. Carter Cathleen Raggio Andreas Zankl Anas M. Khanshour Kristhen N. Atala Jonathan J. Rios Carol A. Wise Ying Zhu Futao Zhang Tony Roscioli Michael Buckley Robert J. Harvey Paul A. Dawson |
| author_facet | Christina G. Tise Katie Ashton Lachlan de Hayr Kun-Di Lee Omkar L. Patkar Emma Krzesinski Jennifer A. Bassetti Erin M. Carter Cathleen Raggio Andreas Zankl Anas M. Khanshour Kristhen N. Atala Jonathan J. Rios Carol A. Wise Ying Zhu Futao Zhang Tony Roscioli Michael Buckley Robert J. Harvey Paul A. Dawson |
| author_sort | Christina G. Tise |
| collection | DOAJ |
| description | Purpose: Sulfate is vital for many physiological processes, including the structural and functional maintenance of macromolecules and formation of sulfur-containing compounds essential for cartilage and bone development. SLC13A1 is a sodium-sulfate cotransporter primarily expressed in the kidney, where it mediates sulfate reabsorption and maintenance of circulating sulfate levels. In this study, we characterized the clinical, biochemical, and functional impact of biallelic SLC13A1 nonsense and/or missense variants in individuals presenting with a skeletal phenotype. Methods: Probands were identified by exome or genome sequencing and GeneMatcher. Sulfate levels were quantified using ion chromatography. SLC13A1 missense variants p.(Arg237Cys), p.(Gly448Asp), p.(Leu516Pro), and p.(Tyr582His) were characterized using bioinformatics, molecular modeling, and [35S]-sulfate uptake assays in Madin-Darby canine kidney cells. Results: All probands presented with concern for short stature and were found to have scoliosis and/or skeletal dysplasia. A reduction in plasma sulfate level and/or increase in urinary sulfate excretion was detected in 2 of 2 probands evaluated. Functional studies were consistent with SLC13A1 variants resulting in the complete loss of sulfate transport activity. Conclusion: Biallelic loss-of-function variants in SLC13A1 are a novel cause of skeletal phenotypes in humans with a measurable biomarker. Sulfate measurements should be considered in the clinical interpretation of variants identified in SLC13A1. |
| format | Article |
| id | doaj-art-fc53c92b96044eb7baa0dc4bcf4c8e7d |
| institution | Kabale University |
| issn | 2949-7744 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genetics in Medicine Open |
| spelling | doaj-art-fc53c92b96044eb7baa0dc4bcf4c8e7d2025-01-26T05:05:27ZengElsevierGenetics in Medicine Open2949-77442025-01-013101958Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasiaChristina G. Tise0Katie Ashton1Lachlan de Hayr2Kun-Di Lee3Omkar L. Patkar4Emma Krzesinski5Jennifer A. Bassetti6Erin M. Carter7Cathleen Raggio8Andreas Zankl9Anas M. Khanshour10Kristhen N. Atala11Jonathan J. Rios12Carol A. Wise13Ying Zhu14Futao Zhang15Tony Roscioli16Michael Buckley17Robert J. Harvey18Paul A. Dawson19Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children’s Hospital and Stanford University, Stanford, CA; Christina G. Tise, Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA 94304.New South Wales Health Pathology, Randwick Genomics, Prince of Wales Hospital, New South Wales, AustraliaSchool of Health, University of the Sunshine Coast, Maroochydore, Queensland, Australia; National PTSD Research Centre, Thompson Institute, University of the Sunshine Coast, Birtinya, QLD, AustraliaMater Research Institute, University of Queensland, Brisbane, QLD, AustraliaMater Research Institute, University of Queensland, Brisbane, QLD, AustraliaMonash Genetics, Monash Medical Centre, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Clayton, VIC, AustraliaDivision of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, NYHospital for Special Surgery, New York, NYHospital for Special Surgery, New York, NYDepartment of Clinical Genetics, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia; Garvan Institute of Medical Research, Darlinghurst, New South Wales, AustraliaCenter for Translational Research, Scottish Rite for Children, Dallas, TX; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TXCenter for Translational Research, Scottish Rite for Children, Dallas, TXCenter for Translational Research, Scottish Rite for Children, Dallas, TX; McDermott Center for Human Growth and Development and the Departments of Orthopaedic Surgery and Pediatrics, University of Texas Southwestern Medical Center, Dallas, TXCenter for Translational Research, Scottish Rite for Children, Dallas, TX; McDermott Center for Human Growth and Development and the Departments of Orthopaedic Surgery and Pediatrics, University of Texas Southwestern Medical Center, Dallas, TXNew South Wales Health Pathology, Randwick Genomics, Prince of Wales Hospital, New South Wales, AustraliaNew South Wales Health Pathology, Randwick Genomics, Prince of Wales Hospital, New South Wales, AustraliaNew South Wales Health Pathology, Randwick Genomics, Prince of Wales Hospital, New South Wales, Australia; Neuroscience Research Australia (NeuRA), Prince of Wales Clinical School, University of New South Wales, Sydney, AustraliaNew South Wales Health Pathology, Randwick Genomics, Prince of Wales Hospital, New South Wales, AustraliaSchool of Health, University of the Sunshine Coast, Maroochydore, Queensland, Australia; National PTSD Research Centre, Thompson Institute, University of the Sunshine Coast, Birtinya, QLD, Australia; Correspondence and requests for materials should be addressed to Robert J. Harvey, School of Health, University of the Sunshine Coast, Maroochydore, Queensland 4556, Australia.Mater Research Institute, University of Queensland, Brisbane, QLD, AustraliaPurpose: Sulfate is vital for many physiological processes, including the structural and functional maintenance of macromolecules and formation of sulfur-containing compounds essential for cartilage and bone development. SLC13A1 is a sodium-sulfate cotransporter primarily expressed in the kidney, where it mediates sulfate reabsorption and maintenance of circulating sulfate levels. In this study, we characterized the clinical, biochemical, and functional impact of biallelic SLC13A1 nonsense and/or missense variants in individuals presenting with a skeletal phenotype. Methods: Probands were identified by exome or genome sequencing and GeneMatcher. Sulfate levels were quantified using ion chromatography. SLC13A1 missense variants p.(Arg237Cys), p.(Gly448Asp), p.(Leu516Pro), and p.(Tyr582His) were characterized using bioinformatics, molecular modeling, and [35S]-sulfate uptake assays in Madin-Darby canine kidney cells. Results: All probands presented with concern for short stature and were found to have scoliosis and/or skeletal dysplasia. A reduction in plasma sulfate level and/or increase in urinary sulfate excretion was detected in 2 of 2 probands evaluated. Functional studies were consistent with SLC13A1 variants resulting in the complete loss of sulfate transport activity. Conclusion: Biallelic loss-of-function variants in SLC13A1 are a novel cause of skeletal phenotypes in humans with a measurable biomarker. Sulfate measurements should be considered in the clinical interpretation of variants identified in SLC13A1.http://www.sciencedirect.com/science/article/pii/S294977442401104XHyposulfatemiaScoliosisShort statureSkeletal dysplasiaSulfate transporter |
| spellingShingle | Christina G. Tise Katie Ashton Lachlan de Hayr Kun-Di Lee Omkar L. Patkar Emma Krzesinski Jennifer A. Bassetti Erin M. Carter Cathleen Raggio Andreas Zankl Anas M. Khanshour Kristhen N. Atala Jonathan J. Rios Carol A. Wise Ying Zhu Futao Zhang Tony Roscioli Michael Buckley Robert J. Harvey Paul A. Dawson Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia Genetics in Medicine Open Hyposulfatemia Scoliosis Short stature Skeletal dysplasia Sulfate transporter |
| title | Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia |
| title_full | Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia |
| title_fullStr | Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia |
| title_full_unstemmed | Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia |
| title_short | Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes, including short stature, scoliosis, and skeletal dysplasia |
| title_sort | biallelic slc13a1 loss of function variants result in impaired sulfate transport and skeletal phenotypes including short stature scoliosis and skeletal dysplasia |
| topic | Hyposulfatemia Scoliosis Short stature Skeletal dysplasia Sulfate transporter |
| url | http://www.sciencedirect.com/science/article/pii/S294977442401104X |
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