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Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice.
Proc Natl Acad Sci U S A. 2011 Nov 15; 108(46):E1146-55.PN

Abstract

Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 (176)RXXR(179)/S(180) proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.

Authors+Show Affiliations

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22006328

Citation

Farrow, Emily G., et al. "Iron Deficiency Drives an Autosomal Dominant Hypophosphatemic Rickets (ADHR) Phenotype in Fibroblast Growth Factor-23 (Fgf23) Knock-in Mice." Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 46, 2011, pp. E1146-55.
Farrow EG, Yu X, Summers LJ, et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A. 2011;108(46):E1146-55.
Farrow, E. G., Yu, X., Summers, L. J., Davis, S. I., Fleet, J. C., Allen, M. R., Robling, A. G., Stayrook, K. R., Jideonwo, V., Magers, M. J., Garringer, H. J., Vidal, R., Chan, R. J., Goodwin, C. B., Hui, S. L., Peacock, M., & White, K. E. (2011). Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proceedings of the National Academy of Sciences of the United States of America, 108(46), E1146-55. https://doi.org/10.1073/pnas.1110905108
Farrow EG, et al. Iron Deficiency Drives an Autosomal Dominant Hypophosphatemic Rickets (ADHR) Phenotype in Fibroblast Growth Factor-23 (Fgf23) Knock-in Mice. Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):E1146-55. PubMed PMID: 22006328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. AU - Farrow,Emily G, AU - Yu,Xijie, AU - Summers,Lelia J, AU - Davis,Siobhan I, AU - Fleet,James C, AU - Allen,Matthew R, AU - Robling,Alexander G, AU - Stayrook,Keith R, AU - Jideonwo,Victoria, AU - Magers,Martin J, AU - Garringer,Holly J, AU - Vidal,Ruben, AU - Chan,Rebecca J, AU - Goodwin,Charles B, AU - Hui,Siu L, AU - Peacock,Munro, AU - White,Kenneth E, Y1 - 2011/10/17/ PY - 2011/10/19/entrez PY - 2011/10/19/pubmed PY - 2012/1/27/medline SP - E1146 EP - 55 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 108 IS - 46 N2 - Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 (176)RXXR(179)/S(180) proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/22006328/Iron_deficiency_drives_an_autosomal_dominant_hypophosphatemic_rickets__ADHR__phenotype_in_fibroblast_growth_factor_23__Fgf23__knock_in_mice_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=22006328 DB - PRIME DP - Unbound Medicine ER -