What is the role of genetics in the etiology of hypophosphatemic rickets?

Updated: May 18, 2020
  • Author: James CM Chan, MD; Chief Editor: Sasigarn A Bowden, MD  more...
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Nonetheless, great strides have been made in studying hypophosphatemic rickets, particularly with the cloning of the mutant gene known as PHEX. [16] The change created in the gene is a loss-of-function mutation, resulting in reduced breakdown and leading to circulatory clearance of a substance known as fibroblast growth factor-23 (FGF23). FGF23 acts on the kidney to cause increased phosphate excretion and decreased alpha-1 hydroxylase activity. The gene product is now known to be a zinc-metallopeptidase. [16, 17, 18]

The PHEX gene, found on the X chromosome, is thought to protect an extracellular matrix glycoprotein (MEPES) from proteolysis through formation of a zinc-dependent protein-protein interaction. A mutated PHEX gene could result in failure to form this interaction, leading to proteolysis and release of the C-terminal ASARM peptide, which possesses phosphaturic and mineralization-inhibiting properties. These 2 mechanisms acting in synergy could account for the massive hyperphosphaturia in this disorder. [17]

A study by Zheng et al indicated that in X-linked hypophosphatemic rickets, the specific type of mutation, ie, truncating or nontrunctating, in the PHEX gene does not correlate with the disease’s clinical presentation and severity. [19]

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