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PHEX, FGF23, DMP1 and beyond.
Curr Opin Nephrol Hypertens. 2008 Jul; 17(4):357-62.CO

Abstract

PURPOSE OF REVIEW

We aim to review the biological properties of novel molecules that are members of a kidney-bone axis involved in the regulation of phosphate homeostasis. In addition, we describe how an improved knowledge of the mechanisms leading to changes in renal phosphate handling may lead to the development of novel therapeutic approaches.

RECENT FINDINGS

As yet, eight genes involved in the regulation of phosphate homeostasis have been identified through genetic studies. A key protein in this regulatory pathway is FGF23, which is made by osteocytes and activates renal KLOTHO/FGFR1 receptor heterodimers to inhibit renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Gain-of-function mutations in FGF23, which render the hormone resistant to proteolytic cleavage, lead to increased phosphaturic activity. Furthermore, inactivating mutations in DMP1 and PHEX increase, through yet unknown mechanisms, FGF23 synthesis and thus enhance renal phosphate excretion. In contrast, loss-of-function mutations in FGF23 and KLOTHO, and abnormal O-glycosylation of FGF23 because of GALNT3 mutations, lead to diminished phosphate excretion. Extremely high levels of FGF23 are observed in chronic renal failure, which may contribute to the development of renal osteodystrophy.

SUMMARY

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis, although it is not yet completely understood how these proteins interact, and additional proteins are likely to contribute to these regulatory events.

Authors+Show Affiliations

Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany. TimStrom@helmholtz-muenchen.deNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

18660670

Citation

Strom, Tim M., and Harald Jüppner. "PHEX, FGF23, DMP1 and Beyond." Current Opinion in Nephrology and Hypertension, vol. 17, no. 4, 2008, pp. 357-62.
Strom TM, Jüppner H. PHEX, FGF23, DMP1 and beyond. Curr Opin Nephrol Hypertens. 2008;17(4):357-62.
Strom, T. M., & Jüppner, H. (2008). PHEX, FGF23, DMP1 and beyond. Current Opinion in Nephrology and Hypertension, 17(4), 357-62. https://doi.org/10.1097/MNH.0b013e3282fd6e5b
Strom TM, Jüppner H. PHEX, FGF23, DMP1 and Beyond. Curr Opin Nephrol Hypertens. 2008;17(4):357-62. PubMed PMID: 18660670.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PHEX, FGF23, DMP1 and beyond. AU - Strom,Tim M, AU - Jüppner,Harald, PY - 2008/7/29/pubmed PY - 2008/11/1/medline PY - 2008/7/29/entrez SP - 357 EP - 62 JF - Current opinion in nephrology and hypertension JO - Curr Opin Nephrol Hypertens VL - 17 IS - 4 N2 - PURPOSE OF REVIEW: We aim to review the biological properties of novel molecules that are members of a kidney-bone axis involved in the regulation of phosphate homeostasis. In addition, we describe how an improved knowledge of the mechanisms leading to changes in renal phosphate handling may lead to the development of novel therapeutic approaches. RECENT FINDINGS: As yet, eight genes involved in the regulation of phosphate homeostasis have been identified through genetic studies. A key protein in this regulatory pathway is FGF23, which is made by osteocytes and activates renal KLOTHO/FGFR1 receptor heterodimers to inhibit renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Gain-of-function mutations in FGF23, which render the hormone resistant to proteolytic cleavage, lead to increased phosphaturic activity. Furthermore, inactivating mutations in DMP1 and PHEX increase, through yet unknown mechanisms, FGF23 synthesis and thus enhance renal phosphate excretion. In contrast, loss-of-function mutations in FGF23 and KLOTHO, and abnormal O-glycosylation of FGF23 because of GALNT3 mutations, lead to diminished phosphate excretion. Extremely high levels of FGF23 are observed in chronic renal failure, which may contribute to the development of renal osteodystrophy. SUMMARY: The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis, although it is not yet completely understood how these proteins interact, and additional proteins are likely to contribute to these regulatory events. SN - 1062-4821 UR - https://www.unboundmedicine.com/medline/citation/18660670/PHEX_FGF23_DMP1_and_beyond_ L2 - https://doi.org/10.1097/MNH.0b013e3282fd6e5b DB - PRIME DP - Unbound Medicine ER -