Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23

Proper serum phosphate concentrations are maintained by a complex and poorl y understood process. Identification of genes responsible for inherited dis orders involving disturbances in phosphate homeostasis may provide insight into the pathways that regulate phosphate balance. Several hereditary disor ders of isolated phosphate wasting have been described, including X-linked hypophosphataemic rickets(1) (XLH), hypophosphataemic bone disease(2) (HBD) , hereditary hypophosphataemic rickets with hypercalciuria(3) (HHRH) and au tosomal dominant hypophosphataemic rickets(4,5) (ADHR). Inactivating mutati ons 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 char acterized by low serum phosphorus concentrations, rickets, osteomalacia, lo wer extremity deformities, short stature, bone pain and dental abscesses(4, 5). Here we describe a positional cloning approach used to identify the ADH R gene which included the annotation of 37 genes within 4 Mb of genomic seq uence. We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23, These mutations in patien ts with ADHR represent the first mutations found in a human FGF gene.