Miscellaneous non-inflammatory musculoskeletal conditions. Hyperphosphatemic familial tumoral calcinosis (FGF23, GALNT3 and αKlotho)

Abstract

Familial tumoral calcinosis (TC) is a rare disorder distinguished by the development of ectopic and vascular calcified masses that occur in settings of hyperphosphatemia (hFTC) and normophosphatemia (nFTC). Serum phosphorus concentrations are relatively tightly controlled by interconnected endocrine activity at the level of the intestine, kidney, and skeleton. Discovering the molecular causes for heritable forms of hFTC has shed new light on the regulation of serum phosphate balance. This review will focus upon the genetic basis and clinical approaches for hFTC, due to genes that are related to the phosphaturic hormone fibroblast growth factor-23 (FGF23). These include FGF23 itself, an FGF23-glycosylating enzyme (GALNT3), and the FGF23 co-receptor α-Klotho (αKL). Our understanding of the molecular basis of hFTC will, in the short term, aid in understanding normal phosphate balance, and in the future, provide potential insight into the design of novel therapeutic strategies for both rare and common disorders of phosphate metabolism.

Figure 1

(top panel) Under normal physiological conditions, increased serum phosphate and 1,25D stimulate FGF23 production in bone, increasing bioactive, intact serum FGF23. FGF23 circulates to the kidney where it binds to a receptor complex comprised of αKlotho and an FGFR in the distal tubule (DT), which then through an unknown mechanism causes a decrease in expression of the sodium phosphate co-transporters, Npt2a and Npt2c, in the proximal tubule (PT) apical membrane. Simultaneously, FGF23 increases expression of the vitamin D catabolic enzyme, 24-hydroxylase, and decreases 1-α-hydroxylase expression. Together, the decrease in Npt2a, Npt2c, and 1,25D leads to a decrease in serum phosphate, which in a negative feedback loop, decreases FGF23 production in the bone. (lower panel) In hFTC, loss of function mutations in either FGF23 or GALNT3 result in decreased intact serum FGF23, and an increase in inactive C-terminal FGF23 fragments. The inactive fragments likely do not signal in the kidney. The αKlotho loss of function mutation leads to a reduction in the activity of the FGF23 receptor signaling complex in the distal tubule. All of the TC mutations likely lead to a release of suppression of Npt2a and Npt2c, a decrease in 24-hydroxylase, and an increase in 1-α-hydroxylase expression, ultimately increasing serum phosphate concentrations, resulting in ectopic and vascular calcifications, and a further stimulus of FGF23 in bone. However, in contrast to FGF23 and GALNT3 mutations, the αKlotho loss of function mutation leads to an increase in serum intact FGF23, as FGF23 protein processing in bone is not directly affected by this mutation.