Sulfate is an ion that is indispensable for human health. It is necessary for the formation of connective tissues, including bone and cartilage.1 The kidney plays a central role in body ion homeostasis by reabsorbing electrolytes from the tubular fluid. Specifically, the proximal tubule is a major site for fluid, protein, and nutrient retrieval.2,3 Our working groups recently described a patient who presented with unexplained chronic chest pain and a kidney stone. By combining clinical and genetic analyses with functional expression assays, our groups demonstrated that the mutation in the sulfate transporter SLC26A1 we identified in this patient impaired the function of this transporter, thereby causing sulfate deficiency due to sulfate loss into the urine.4 To extend these findings to a population level, we used genetic data of >5,000 individuals and identified 43 variants in the SCL26A1 gene. Of note, variants affecting transporter function were significantly associated with lower plasma sulfate concentrations. In view of recent evidence by others linking sulfate homeostasis to bone disorders, we concluded that the kidney may play an important role in musculoskeletal health by retaining sulfate in the body. The current research proposal seeks to examine the role of the sulfate transporter SLC26A1 in musculoskeletal health in more depth.
During the last three months, we identified a second patient with a novel, homozygous SLC26A1 mutation. The patient has been suffering from aortic root dilatation, early cataract formation, and increased arm length. Based on his clinical symptoms the diagnosis of Marfan syndrome was made. However, testing for known genes involved in Marfan syndrome has not yielded any results. We identified a novel mutation of the sulfate transporter gene SLC26A1 in the affected patient. The doctoral thesis will examine the hypothesis that a defect in SLC26A1-mediated sulfate transport may explain the patient’s clinical symptoms. In a first step, the doctoral student will be examining whether the novel mutation in fact leads to a sulfate transport defect by comparing radioactive sulfate fluxes in Xenopus laevis oocytes expressing WT and mutant transporter. In a second step, the doctoral student will examine kidney tubuloids derived from the patient. To this end, pluripotent stem cells (iPSC) will be programmed to kidney tubuloids and examined for sulfate transport. Lastly, we would like to examine cartilage formation in the patient and in SLC26A1-deficient mice.
Aim 1: Functional analyses of the detected SLC26A1 mutation in Xenopus laevis oocytes.
Aim 2: Characterization of sulfate transport in kidney tubuloids from patient-derived pluripotent stem cells.
Aim 3: Assess bone health and cartilage formation in the patient and SLC26A1-deficient mice.