ECTS2013 Poster Presentations Calciotropic and phosphotropic hormones and mineral metabolism (33 abstracts)
Interaction between FGF23 R176W mutation and C716T nonsynonymous change (T239M, rs7955866) in FGF23 on the clinical phenotype in a family with autosomal dominant hypophosphatemic rickets
Daniela Merlotti 1 , Domenico Rendina 2 , Luigi Gennari 1 , Teresa Esposito 3 , Sara Magliocca 3 , Gianpaolo De Filippo 2 , Pasquale Strazzullo 2 , Ranuccio Nuti 2 & Fernando Gianfrancesco 1,
1Department of Medical Surgical Sciences and Neurosciences, University of Siena, Siena, Italy; 2Department of Clinical and Experimental Medicine, University of Naples Federico II, Naples, Italy; 3Institute of Genetics and Biophysics, CNR, Naples, Italy.
Autosomal dominant hypophosphatemic rickets (ADHR) is a hereditary disorder characterized by isolate renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25(OH)2D3 levels. ADHR is caused by mutations in FGF23 protein that actively regulates phosphate homeostasis. In contrast to X-linked dominant hypophosphatemic rickets, ADHR shows incomplete penetrance, variable age at onset, and in rare cases resolution of the phosphate-wasting defect. In an Italian family showing clinical and biological features of ADHR, we identified a heterozygous C526T mutation leading to the R176W amino acid replacement in the consensus sequence for the proteolytic cleavage domain of the FGF23 protein. The mutation was observed in two members of this family: i) a 44 years old female with clinical onset after pregnancy (renal phosphate leak, high FGF23 levels, bone pain and spontaneous bone fractures), and ii) her 16 years old female, daughter, without any clinical or biochemical characteristic of ADHR. History of ADHR was also described in a nephew of patient 1, with clinical onset at age 13. Interestingly, screening of the entire region of FGF23 led to the identification of an additional functional FGF23T239M polymorphic variant which is associated with higher FGF23 levels and hypophosphatemia in the general population. This variant was present in patient 1 (heterozygous carrier) but not in patient 2. Previous in vitro studies demonstrated that the FGF23C526T mutation protect FGF23 from proteolysis, elevating FGF23 concentrations and leading to phosphate wasting in ADHR. Moreover we also demonstrated that the polymorphic T239M change increases FGF23 secretion and that the FGF23239M variant induces a higher activation of the FGF receptor/ERK pathway compared to FGF23239T. Thus, given the residual activity of proteolytic enzyme on the mutant FGF23C526T, we suggest that enhanced FGF23 levels associated with the T239M change in patient 1 may explain the variable clinic phenotype observed in this family and possibly other ADHR families.
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ISSN 2052-1219 (online)
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