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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/E929    most recent 90456.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Garringer, H. J. Articles by White, K. E. Search for Related Content PubMed PubMed Citation Articles by Garringer, H. J. Articles by White, K. E.

Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis

¹Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana; ²Department of Orthopedics, Imam Khomeini University Hospital, Tehran University of Medical Sciences, Tehran, Iran; and ³Howard Hughes Medical Institute, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 21 May 2008 ; accepted in final form 3 August 2008

Fibroblast growth factor 23 (FGF23) is a hormone required for normal renal phosphate reabsorption. FGF23 gain-of-function mutations result in autosomal dominant hypophosphatemic rickets (ADHR), and FGF23 loss-of-function mutations cause familial hyperphosphatemic tumoral calcinosis (TC). In this study, we identified a novel recessive FGF23 TC mutation, a lysine (K) substitution for glutamine (Q) (160 C > A) at residue 54 (Q54K). To understand the molecular consequences of all known FGF23-TC mutants (H41Q, S71G, M96T, S129F, and Q54K), these proteins were stably expressed in vitro. Western analyses revealed minimal amounts of secreted intact protein for all mutants, and ELISA analyses demonstrated high levels of secreted COOH-terminal FGF23 fragments but low amounts of intact protein, consistent with TC patients' FGF23 serum profiles. Mutant protein function was tested and showed residual, yet decreased, bioactivity compared with wild-type protein. In examining the role of the FGF23 COOH-terminal tail (residues 180–251) in protein processing and activity, truncated mutants revealed that the majority of the residues downstream from the known FGF23 SPC protease site (₁₇₆RXXR₁₇₉/S₁₈₀) were not required for protein secretion. However, residues adjacent to the RXXR site (between residues 188 and 202) were required for full bioactivity. In summary, we report a novel TC mutation and demonstrate a common defect of reduced FGF23 stability for all known FGF23-TC mutants. Finally, the majority of the COOH-terminal tail of FGF23 is not required for protein secretion but is required for full bioactivity.

fibroblast growth factor 23; phosphate; hyperphosphatemia; Klotho