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.
|Original language||English (US)|
|Number of pages||6|
|Journal||Biochimica et Biophysica Acta - Molecular Basis of Disease|
|State||Published - Sep 2009|
Bibliographical noteFunding Information:
We are grateful to our patients and their family members for their enthusiastic, and continuous support. We would like also to thank many collaborators for their invaluable contribution to the various studies reviewed above including Orit Topaz, Gabriele Richard, Margarita Indelman, Aryeh Metzker, Ulla Mandel, Mordechai Mizrachi, John G. Cooper, Polina Specktor, Vered Friedman, Gila Maor, Israel Zelikovic, Sharon Raimer, Yoram Altschuler, Mordechai Choder, Dani Bercovich, Jouni Uitto and Reuven Bergman. This work was supported in part by grants provided by the Israel Science Foundation, the Rappaport Institute for Research in the Medical Sciences, Technion, and NIH/NIAMS grant R01 AR052627.