Endocrine Abstracts

Despite its broad biological importance, the regulation of phosphate homeostasis remains incompletely understood. Important new insights into underlying mechanisms were made by defining the molecular basis of different inherited disorders characterized by an abnormal regulation of phosphate homeostasis. These efforts have led to the identification of three novel regulators of phosphate homeostasis, namely PHEX, FGF23, GALNT3. Additional studies have furthermore revealed heterozygous mutations in NaPi-IIa in some patients with hypophosphatemia and osteoporosis, and homozygous or compound heterozygous mutations in NaPi-IIc appear to be the cause of hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Using recently developed immunometric assays, intact and C-terminal FGF23 levels are elevated in patients with oncogenic osteomalacia (OOM) and the tumors that cause this disease overexpress FGF23 mRNA. Intact and C-terminal FGF23 levels are furthermore elevated in patients with X-linked hypophosphatemia, a disease caused by inactivating PHEX mutations suggesting that the encoded endopeptidase has a role in degrading intact FGF23. Surprisingly, C-terminal FGF23 levels, but not intact FGF23 levels, were found to be dramatically elevated in patients with two forms of tumoral calcinosis. One form is caused by homozygous, inactivating GALNT3 mutations implying that the encoded enzyme, which is involved in the initiation of O-glycosylation, has important an important role in preventing cleavage of FGF23 into biologically inactive fragments. Consistent with this hypothesis, a second form of this disease was found to be caused by different homozygous FGF23 mutations, which all affect conserved serine residues that may undergo O-glycosylation by GALNT3; these mutations also lead to an abnormal processing of FGF23 and thus increased secretion of C-terminal fragments. Despite these advances, it remains largely unknown how most of the different proteins mentioned above contribute to the regulation of phosphate homeostasis and it is almost certain that additional proteins are involved in this process.