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Journal article
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, Vol.3, pp.1-13
2025
Abstract
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 co-transporter 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 MDCK 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 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.
Details
- Title
- Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes including short stature, scoliosis, and skeletal dysplasia
- Authors
- Christina G. Tise (Corresponding Author) - Stanford UniversityKatie Ashton - Prince of Wales HospitalLachlan de Hayr - University of the Sunshine Coast, Queensland, School of Health - BiomedicineKun-Di Lee - The University of QueenslandOmkar L. Patkar - The University of QueenslandEmma Krzesinski - Monash Medical CentreJennifer A. Bassetti - Weill Cornell MedicineErin M. Carter - Hospital for Special SurgeryCathleen Raggio - Hospital for Special SurgeryAndreas Zankl - Children's Hospital at WestmeadAnas M. Khanshour - The University of Texas Southwestern Medical CenterKristhen N. Atala - Texas Scottish Rite Hospital for ChildrenJonathan J. Rios - Texas Scottish Rite Hospital for ChildrenCarol A. Wise - Texas Scottish Rite Hospital for ChildrenYing Zhu - Prince of Wales HospitalFutao Zhang - Prince of Wales HospitalTony Roscioli - Prince of Wales HospitalMichael Buckley - Prince of Wales HospitalRobert J. Harvey - University of the Sunshine Coast, Queensland, School of HealthPaul A. Dawson (Corresponding Author) - The University of Queensland
- Publication details
- Genetics in Medicine Open, Vol.3, pp.1-13
- Publisher
- Elsevier Inc.
- Date published
- 2025
- DOI
- 10.1016/j.gimo.2024.101958
- ISSN
- 2949-7744; 1098-3600
- Organisation Unit
- School of Health - Biomedicine; School of Health
- Language
- English
- Record Identifier
- 991091101502621
- Output Type
- Journal article
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