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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 rickets1 (XLH), hypophosphataemic bone disease2 (HBD), hereditary hypophosphataemic rickets with hypercalciuria3 (HHRH) and autosomal dominant hypophosphataemic rickets4,5 (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 abscesses4,5. 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.

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Figure 1: Mutation analysis.
Figure 2: Physical map of the ADHR critical region.
Figure 3: Sequence alignment between FGF23 and the other mammalian FGF family members.
Figure 4: Tissue expression of FGF23.

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Acknowledgements

We thank the patients and their families for participation; the Albert Einstein College of Medicine Human Genome Center and the Baylor College of Medicine Human Genome Sequencing Center for generation and open dissemination of human genomic sequence data; R. Hubel for assistance with mutation screening; B. Lanske for performing in situ hybridization and providing mouse cDNA; P. Freisinger for preparing human cartilage cell cultures; and D. Wölfel and K. Kruse for sending DNA samples. This work was supported by the Deutsche Forschungsgemeinschaft (STR304/2-1) and NIH grants AR42228, AG05793, AR02095 and NS26630, and National Research Service Award AR08550 (K.E.W.).

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Correspondence to Michael J. Econs or Tim M. Strom.

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White, K., Evans, W., O'Riordan, J. et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26, 345–348 (2000). https://doi.org/10.1038/81664

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