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Review
. 2009 Sep;1792(9):847-52.
doi: 10.1016/j.bbadis.2008.10.008. Epub 2008 Oct 25.

Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis

Ilana Chefetz  1 , Eli Sprecher
Affiliations
Review

Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis

Ilana Chefetz et al. Biochim Biophys Acta. 2009 Sep.

Abstract

Familial tumoral calcinosis refers to a group of disorders inherited in an autosomal recessive fashion. Hyperphosphatemic tumoral calcinosis is characterized by increased re-absorption of phosphate through the renal proximal tubule, resulting in elevated phosphate concentration and deposition of calcified deposits in cutaneous and subcutaneous tissues, as well as, occasionally, in visceral organs. The disease was found to result from mutations in at least 3 genes: GALNT3, encoding a glycosyltransferase termed ppGalNacT3, FGF23 encoding a potent phosphaturic protein, and KL encoding Klotho. Recent data showed that ppGalNacT3 mediates O-glycosylation of FGF23, thereby allowing for its secretion and possibly protecting it from proteolysis-mediated inactivation. Klotho was found to serve as a co-receptor for FGF23, thereby integrating the genetic data into a single physiological system. The elucidation of the molecular basis of HFTC shed new light upon the mechanisms regulating phosphate homeostasis, suggesting innovative therapeutic strategies for the management of hyperphosphatemia in common acquired conditions such as chronic renal failure.

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Figures

Fig. 1
Fig. 1
Role of ppGalNacT3, FGF23 and Klotho in the maintenance of phosphate homeostasis. ppGalNacT3 mediates O-glycosylation of FGF23, thereby protecting it from degradation through proteolysis. Klotho serves as a co-receptor for FGF23. Accordingly, mutations in anyone of these three genes, result in decreased FGF23 activity, increased phosphate re-absorption and consequently, hyperphosphatemia with tumoral calcinosis.
Fig. 2
Fig. 2
Doxycycline up-regulates ppGalNacT3 expression in SaOs cells.
See this image and copyright information in PMC

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