Molecular Genetics of Inherited Hypophosphataemias
Authors: Negri Armando Luis 
Published: December 2008

Hypophosphataemia due to isolated renal phosphate wasting comprises a genetically heterogeneous group of diseases, generally associated with rickets and osteomalacia. These inherited disorders comprise X‐linked hypophosphataemic rickets (XLH), autosomal dominant hypophosphataemic rickets (ADHR), autosomal recessive hypophosphataemic rickets (ARHR) and hereditary hypophosphataemic rickets with hypercalciuria (HHRH). XLH is the most common disorder. The gene mutated is

PHEX

(from
Ph
osphate‐regulating gene with homologies to
e
ndopeptidades on
X
‐chromosome) which encodes an ectoenzyme of the endopeptidase family. The phosphaturic factor FGF23 (fibroblast growth factor) was found increased in XLHs and is also increased in its closely related animal model, the HYP mouse. ADHR clinically resembles XLH. The disease results from accumulation of mutated FGF23 because of impaired proteolytic degradation. ARHR results from homozygous mutations in

DMP1

(dentin matrix protein 1) gene, which encodes a noncollagenous bone matrix protein DMP1.In this disease, FGF23 is elevated, suggesting that DMP1 may regulate FGF23 expression. Finally, HHRH results in mutations in

SLC34A3

, the gene encoding the renal sodium‐phosphate cotransporter NaPi‐IIc.

Key concepts

Hypophosphataemia due to isolated renal phosphate wasting is a genetically heterogeneous group of diseases. They differ from one another not only in their mode of inheritance but also in their clinical features, metabolism of vitamin D and response to therapy.

At least five inherited disorders have been described including X‐linked hypophosphataemic rickets (XLH), autosomal dominant hypophosphataemic rickets (ADHR) or a related disorder known as hypohosphataemic bone disease (HBD), autosomal recessive hypophosphataemic rickets (ARHR) and hereditary hypophosphataemic rickets with hypercalciuria (HHRH).

XLH is the most common of the inherited renal phosphate wasting disorders. The gene mutated ion this disease is
PHEX
(from
Ph
osphate regulating gene with homologies to
e
ndopeptidades on
X
‐chromosome).

PHEX gene encodes a protein that closely resembles other members of the endopeptidase family. It is likely that PHEX functions either to activate or degrade a peptide hormone or related factor.

ADHR it produced by mutations in the phosphatonin FGF23 (fibroblast growth factor). The mutations that cause ADHR occur in either of two arginine residues in an RXXR motif. This motif is the site for cleavage of FGF23 by a protease of the prohormone convertase class. FGF23 accumulates in patients with ADHR because its clearance by proteolytic degradation is impaired.

ARHR is produced by mutations in
DMP1
(dentin matrix protein 1) gene, which encodes a noncollagenous bone matrix protein. DMP1, is a member of the SIBLING (Small Integrin‐Binding LIgand
N
‐linked Glycoprotein) family of secreted acidic extracellular glycophosphoproteins highly expressed in mineralized tissues, specially in osteocytes.

Intact plasma levels of the phosphatonin FGF23 are elevated in patients with ARHR, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)(2)D levels found in this disease, and suggesting that DMP1 may regulate FGF23 expression.

DMP1 has multiple roles in the regulation of postnatal mineralization through direct effects on mineral formation and crystal growth, and indirect effects on Ca×P concentrations and bone matrix turnover.

HHRH is distinct from other forms of hypophosphataemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25‐dihydroxyvitamin D levels and increased intestinal calcium absorption.

HHRH was mapped to a 1.6‐Mbp region on chromosome 9q34, which contains
SLC34A3
, the gene encoding the renal sodium‐phosphate cotransporter NaPi‐IIc. NaPi‐IIc has a key role in the regulation of phosphate homeostasis in the proximal tubule.