Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes including short stature, scoliosis, and skeletal dysplasia

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

doi:10.1016/j.gimo.2024.101958

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Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes including short stature, scoliosis, and skeletal dysplasia

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Biallelic SLC13A1 loss-of-function variants result in impaired sulfate transport and skeletal phenotypes including short stature, scoliosis, and skeletal dysplasia

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, …

Genetics in Medicine Open, Vol.3, pp.1-13

2025

DOI: https://doi.org/10.1016/j.gimo.2024.101958

PMCID: PMC11803892

PMID: 39925707

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Abstract

hyposulfatemia

scoliosis

short stature

skeletal dysplasia

sulfate transporter

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.

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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 University
Katie Ashton - Prince of Wales Hospital
Lachlan de Hayr - University of the Sunshine Coast, Queensland, School of Health - Biomedicine
Kun-Di Lee - The University of Queensland
Omkar L. Patkar - The University of Queensland
Emma Krzesinski - Monash Medical Centre
Jennifer A. Bassetti - Weill Cornell Medicine
Erin M. Carter - Hospital for Special Surgery
Cathleen Raggio - Hospital for Special Surgery
Andreas Zankl - Children's Hospital at Westmead
Anas M. Khanshour - The University of Texas Southwestern Medical Center
Kristhen N. Atala - Texas Scottish Rite Hospital for Children
Jonathan J. Rios - Texas Scottish Rite Hospital for Children
Carol A. Wise - Texas Scottish Rite Hospital for Children
Ying Zhu - Prince of Wales Hospital
Futao Zhang - Prince of Wales Hospital
Tony Roscioli - Prince of Wales Hospital
Michael Buckley - Prince of Wales Hospital
Robert J. Harvey - University of the Sunshine Coast, Queensland, School of Health
Paul 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
PMID: 39925707; PMC11803892
Organisation Unit: School of Health - Biomedicine; School of Health
Language: English
Record Identifier: 991091101502621
Output Type: Journal article

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