Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23

Abstract

Proper serum phosphate concentrations are maintained by a complex and poorly understood process. Identification of genes responsible for inherited disorders involving disturbances in phosphate homeostasis may provide insight into the pathways that regulate phosphate balance. Several hereditary disorders of isolated phosphate wasting have been described, including X-linked hypophosphataemic rickets (XLH), hypophosphataemic bone disease (HBD), hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and autosomal dominant hypophosphataemic rickets (ADHR). Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH (refs 6,7). ADHR (MIM 193100) is characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses. Here we describe a positional cloning approach used to identify the ADHR gene which included the annotation of 37 genes within 4 Mb of genomic sequence. We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23. These mutations in patients with ADHR represent the first mutations found in a human FGF gene.

MEPE has the properties of an osteoblastic phosphatonin and minhibin

“…There is overwhelming evidence implicating the osteoblast as the cell intrinsically defective [13,18,[20][21][22]30,37,50,58,59,67,69,80,101,102] and the HYP osteoblast directly secretes factors (phosphatonins) that impact adversely on renal phosphate uptake and mineralization in vivo and in vitro. FGF23 activating mutations are responsible for the changes in phosphate, vitamin D metabolism and mineralization in ADHR [4,82,97,98] and overexpression of wild-type FGF23 in some but not all OHO tumors is directly or indirectly responsible for the changes in some tumor-induced osteomalacias [15,81,97,99]. Also, a number of groups have reported lack of FGF23 expression in bone/osteoblasts [3,27,29,41,98,104] and others using more sensitive techniques have detected low levels of FGF23 mRNA in bone tissue but not in normal murine osteoblasts [40].…”

“…FGF23 activating mutations are responsible for the changes in phosphate, vitamin D metabolism and mineralization in ADHR [4,82,97,98] and overexpression of wild-type FGF23 in some but not all OHO tumors is directly or indirectly responsible for the changes in some tumor-induced osteomalacias [15,81,97,99]. Also, a number of groups have reported lack of FGF23 expression in bone/osteoblasts [3,27,29,41,98,104] and others using more sensitive techniques have detected low levels of FGF23 mRNA in bone tissue but not in normal murine osteoblasts [40]. This suggests a complex pathway involving extra-osteoblastic phosphatonins (EO-PTN) and osteoblastic phosphatonins (OB-PTN) in Hyp.…”

“…Recent discoveries have confirmed that autosomal dominant hypophosphatemic rickets (ADHR) is caused by activating mutations in FGF23 [4,82,97,98]. The specific ADHR mutations increase the stability of mutated FGF23 and the uncleaved mutated molecule is phosphaturic and elicits osteomalacia/rickets [4,77,81,98].…”

“…The specific ADHR mutations increase the stability of mutated FGF23 and the uncleaved mutated molecule is phosphaturic and elicits osteomalacia/rickets [4,77,81,98]. Wild-type FGF23 is also expressed in OHO tumors and the tumor over-expression of the wild-type FGF23 molecule is thought to swamp proteolytic mechanisms that normally inactivate full-length FGF23 [11,15,81].…”

Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia

“…It is interesting to note that the responsible gene for ADHR has been recently identified and named FGF23 (17). The missense mutations at 176 Arg and 179 Arg are responsible for ADHR.…”