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Published on: September 30, 2019
Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and
Shoji Ichikawa1, Andrea H Sorenson, Anthony M Austin
1Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5121, USA.
Abstract:
Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia. The disease is caused by inactivating mutations in fibroblast growth factor 23 (FGF23), Klotho (KL), and uridine diphosphate-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). In vitro studies indicate that GALNT3 O-glycosylates a phosphaturic hormone, FGF23, and prevents its proteolytic processing, thereby allowing secretion of intact FGF23. In this study we generated mice lacking the Galnt3 gene, which developed hyperphosphatemia without apparent calcifications. In response to hyperphosphatemia, Galnt3-deficient mice had markedly increased Fgf23 expression in bone. However, compared with wild-type and heterozygous littermates, homozygous mice had only about half of circulating intact Fgf23 levels and higher levels of C-terminal Fgf23 fragments in bone. Galnt3-deficient mice also exhibited an inappropriately normal 1,25-dihydroxyvitamin D level and decreased alkaline phosphatase activity. Furthermore, renal expression of sodium-phosphate cotransporters and Kl were elevated in Galnt3-deficient mice. Interestingly, there were sex-specific phenotypes; only Galnt3-deficient males showed growth retardation, infertility, and significantly increased bone mineral density. In summary, ablation of Galnt3 impaired secretion of intact Fgf23, leading to decreased circulating Fgf23 and hyperphosphatemia, despite increased Fgf23 expression. Our findings indicate that Galnt3-deficient mice have a biochemical phenotype of tumoral calcinosis and provide in vivo evidence that Galnt3 plays an essential role in proper secretion of Fgf23 in mice.
Insights
Familial tumoral calcinosis is linked to mutations in GALNT3. Ablating Galnt3 in mice caused hyperphosphatemia and impaired FGF23 secretion, providing in vivo evidence for GALNT3
Area of Science:
- Genetics and Molecular Biology
- Endocrinology
- Mineral Metabolism
Background:
- Familial tumoral calcinosis (FTC) presents with ectopic calcifications and hyperphosphatemia.
- Mutations in FGF23, KL, and GALNT3 genes are implicated in FTC.
- GALNT3 is hypothesized to O-glycosylate FGF23, preventing its degradation and enabling secretion.
Purpose of the Study:
- To investigate the in vivo role of Galnt3 in FGF23 secretion and tumoral calcinosis pathogenesis.
- To characterize the physiological consequences of Galnt3 deficiency in a mouse model.
Main Methods:
- Generation of Galnt3-deficient mice.
- Biochemical analysis of serum and bone parameters (phosphate, FGF23, vitamin D, alkaline phosphatase).
- Assessment of renal gene expression and phenotypic characterization, including growth and fertility.
Main Results:
- Galnt3-deficient mice exhibited hyperphosphatemia but lacked calcifications.
- Impaired secretion of intact FGF23 and increased C-terminal fragments were observed.
- Sex-specific phenotypes included growth retardation and infertility in males.
Conclusions:
- Galnt3 is essential for the proper secretion of intact FGF23 in mice.
- Galnt3 deficiency leads to a biochemical phenotype resembling tumoral calcinosis.
- These findings highlight GALNT3's critical role in regulating FGF23 metabolism and phosphate homeostasis.
