Phosphate-regulating endopeptidase homolog X-linked also known as phosphate-regulating gene with homologies to endopeptidases on the X chromosome or metalloendopeptidase homolog PEX is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the PHEX

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. This gene contains 18

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s and is located on the

X chromosome The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...

Function

The protein encoded by this gene is a transmembrane

endopeptidase Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids. For this r ...

that belongs to the type II integral membrane zinc-dependent endopeptidase family. The protein is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption. The bone and dentin protein

osteopontin Osteopontin (OPN), also known as bone /sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric), is a protein that in humans is encoded by the ''SPP1'' gene (sec ...

(OPN) which inhibits mineralization in the skeleton and in teeth is a substrate for PHEX. In the absence of functional PHEX in the mouse model (Hyp) of X-linked hypophosphatemia (XLH), and in human XLH where PHEX activity is decreased or absent, increased circulating FGF23 hormone results in low serum phosphate (caused by renal phosphate wasting) such that there is an insufficient level of this mineral ion in the blood in transit to mineralized tissues compared to the normal amount that is required for proper bone and tooth mineralization; this leads to soft bones and teeth. In addition to renal phosphate wasting, the mineralization-inhibiting phosphoprotein osteopontin and osteopontin fragments accumulate in the extracellular matrix of bones and teeth to contribute locally to the reduction in mineralization, which together with the systemic lower level of circulating serum phosphate, both lead to the decreased mineralization (hypomineralization) characteristic of the

osteomalacia Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of b ...

and odontomalacia typically seen in XLH/Hyp. XLH patients have soft and deformed skeletons, and soft teeth that easily become infected. Osteopontin (OPN) is a substrate protein for the enzyme PHEX whose enzymatic activity degrades/removes the mineralization-inhibiting function of OPN in normal mineralized tissue physiology, In disease, when the PHEX gene is mutated causing reduced or absent PHEX enzymatic activity, OPN that would normally be degraded and cleared remains behind in the extracellular matrix of bones and teeth, accumulating locally in the tissue to contribute to the osteomalacia and odontomalacia. A relationship describing local, physiologic double-negative (inhibiting inhibitors) regulation of mineralization involving OPN has been termed the ''Stenciling Principle'' of mineralization, whereby enzyme-substrate pairs imprint mineralization patterns into the extracellular matrix (most notably for bone) by degrading mineralization inhibitors (''e.g''. TNAP/TNSALP/ALPL enzyme degrading the pyrophosphate inhibition, and PHEX enzyme degrading the osteopontin inhibition). The ''Stenciling Principle'' for mineralization is particularly relevant to the osteomalacia and odontomalacia observed in hypophosphatasia and X-linked hypophosphatemia.

Clinical significance

Mutation of PHEX leads to

X-linked hypophosphatemia Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). Genes situated on the X-chromosome are thus termed X-linked, and a ...

References

EC 3.4.24 {{gene-X-stub