Serum metabolic profiling analysis of Gitelman syndrome using untargeted metabolomics

Gitelman syndrome (GS) is a rare hereditary kidney disorder characterized by electrolyte abnormalities. However, its systemic manifestations, such as growth retardation, suggest broader metabolic disturbances. To investigate this issue, we explored the link between GS and lipid metabolism, hypothesizing that the genetic mutation affects pathways beyond renal function. Our study focused on five pediatric GS patients carrying homozygous SLC12A3 c.1262G > T mutation and seven healthy, age-matched controls from the Yi ethnic group. Consistent with systemic involvement, these children exhibited impaired growth and significantly lower serum total cholesterol compared to healthy controls. To determine whether this mutation directly causes cholesterol metabolism abnormalities, we conducted in vitro. 293 T cell with the c.1262G > T point mutation showed reduced intracellular cholesterol storage and increased cholesterol efflux, confirming a direct role of the mutation in disrupting cholesterol metabolism. Returning to our patient samples, we performed untargeted serum metabolomics to obtain a comprehensive view of metabolic changes. This analysis revealed alterations in numerous lipid-related metabolites. Crucially, glycerophospholipid metabolism was identified as the most significantly perturbed pathway in GS patients. These findings provide the first clear evidence linking this renal tubulopathy to systemic dyslipidemia, fundamentally expanding our understanding of its pathophysiology.