The genetic polymorphism of XPR1 associated with Fanconi syndrome in Chinese patients with X-linked hypophosphatemia.

Purpose: X-linked hypophosphatemia (XLH) is the most common type of hereditary hypophosphatemic rickets caused by elevated fibroblast growth factor 23 (FGF23). Multiple cases have reported XLH had Fanconi syndrome (FS) with unidentified mechanism. We investigated the association between genetic polymorphisms of phosphate transporters in renal proximal tubules and XLH with FS for the first time.

Methods: 25 Chinese XLH patients with FS (XLH-FS) and 33 patients without any urine abnormalities (XLH-nonFS) were included. We collected their clinical manifestations and laboratory results, screened the single-nucleotide polymorphisms (SNPs) of XPR1, SLC34A1 and SLC34A3 by a next generation sequencing-based method, and analyzed the correlation between SNPs and XLH with FS. Computational predictions identified microRNAs (miRNAs) targeting SNPs that influenced susceptibility of FS, and confirmed their interaction and impact on gene expression by a dual-luciferase reporter system.

Results: XLH-FS group had a higher proportion of trouble walking (88.0% vs 51.5%, p = 0.003). Among the 17 SNPs, rs10494535 located within 3'-UTR region of XPR1 showed significant difference between the two groups. TT/CT genotype and T allele increased susceptibility of FS. Lower luciferase activities were observed in dual-luciferase reporter gene assay as rs10494535 T allele and rs148196667 C allele binding with miRNAs respectively, which implied decreases in XPR1 expression.

Conclusion: XLH with FS had greater mobility difficulties. The genetic polymorphism of XPR1 was associated with FS in XLH patients. Susceptibility of FS in XLH patients was possibly related to the decrease expression of XPR1 due to the interaction between SNPs and miRNAs.