Genetics of Phosphate Regulation Disorders

Abstract

Phosphate is an abundant anion in humans and plays an important role in many metabolic processes. Maintenance of phosphate homoeostasis is critical, and kidney plays an important role in the regulation of phosphate homoeostasis. Phosphate reabsorption by the kidney is the final determinant of serum phosphate levels. Fibroblast growth factor 23 (FGF23), parathyroid hormone and Klotho are important hormones that regulate phosphate homoeostasis. Dysregulation of FGF23 is the most common inherited cause of hypophosphatemic and hyperphosphatemic disorders. Mutations of sodium phosphate cotransporters, responsible for phosphate reabsorption, also result in inherited disorders of phosphate homoeostasis. Recent discoveries in the field of FGF23 have led to better understanding of the pathophysiology of many of the inherited hypophosphatemic and hyperphosphatemic disorders.

Key Concepts:

  • Maintenance of normal phosphate homoeostasis is integral for many bodily functions.

  • Both hyperphosphatemia and hypophosphatemia have detrimental effects.

  • Fibroblast growth factor 23 (FGF23), parathyroid hormone and Klotho are well‐known phosphaturic hormones.

  • Sodium phosphate cotransporters (NaPi‐2a and NaPi‐2c) that are present in the proximal tubule of the kidney are the final regulators of phosphate reabsorption. Mutations of sodium phosphate cotransporters result in hypophosphatemia.

  • Disturbances in hormones such as FGF23, parathyroid hormone and Klotho result in many inherited hypophosphatemic and hyperphosphatemic disorders.

  • X‐linked hypophosphatemic rickets is the most common form of inherited rickets in children and is due to excess FGF23.

  • Autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia and osteoglophonic dysplasia are also inherited hypophosphatemic disorders resulting from excessive FGF23.

  • Tumoural calcinosis is an inherited hyperphosphatemic disorder resulting from decreased FGF23 activity.

Keywords: hypophosphatemia; hyperphosphatemia; parathyroid hormone; fibroblast growth factor 23; Klotho

Figure 1.

Proposed Interaction of FGF23 with FGF receptors and Klotho to initiate intracellular signalling to decrease phosphate transport in the proximal tubule and to decrease the synthesis of 1,25(OH)2 Vitamin D3.

Adapted with permission from Gattineni and Baum 2012. © Springer.
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Gattineni, Jyothsna(Sep 2013) Genetics of Phosphate Regulation Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024270]