A point mutation in the GALNT3 gene causes a dramatic shift in fibroblast growing factor 23 stability and function
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| Rok publikování | 2025 |
| Druh | Konferenční abstrakty |
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| Popis | Phosphate homeostasis in mammals critically depends on fibroblast growth factor 23 (FGF23), a hormone that reduces renal phosphate reabsorption in the kidneys. Its biological activity relies on an intact, fully O-glycosylated form mediated by the N-acetylgalactosaminyl-transferase 3 (ppGalNAcT3), encoded by the GALNT3 gene. Reduced levels of intact FGF23 are a hallmark of hyperphosphatemic familial tumoral calcinosis (HFTC). We aimed to evaluate the impact of a specific GALNT3 point mutation that inactivates ppGalNAcT3 on hormone regulation and the impact of the disrupted FGF23 stability on calcium-phosphate metabolism in a mouse carrying this mutation. In our pilot experiment, we analyzed plasma from six groups of mice (homozygous, heterozygous, and wild-type; eight males and eight females per group) collected from the retro-orbital sinus. Both intact and total (C-terminal) FGF23 levels were quantified using ELISA. Mice with inactive ppGalNAcT3 exhibited significantly decreased levels of intact FGF23 and markedly elevated levels of total FGF23, indicating increased proteolytic cleavage. Analysis revealed no sex-based differences across groups. Intact FGF23 levels were significantly lower in homozygous mutants than in both heterozygous and wild-type mice (p < 0.0001 and p < 0.05, respectively), while total FGF23 levels were extremely elevated in homozygous mice relative to the other groups (p < 0.0001). A highly significant increase in total FGF23 was also observed in heterozygotes compared to wild-type mice (p < 0.01). These findings confirm that ppGalNAcT3-mediated glycosylation is critical for FGF23 stability and that its disruption—caused here by a point mutation in the GALNT3 gene—leads to a profound hormonal imbalance. This mechanism, uncovered using our genetically defined mouse model, provides a valuable tool for dissecting the molecular pathogenesis of phosphate-related disorders such as HFTC. Importantly, our results suggest that therapeutic substitution of intact FGF23 could potentially restore hormonal and mineral balance, offering a promising strategy for treating not only rare genetic diseases, but also broader disorders of calcium-phosphate metabolism. |
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