PHEX

PHEX, short for phosphate-regulating gene with homology to endopeptidases on the X chromosome, is a human gene encoding a membrane-bound zinc-dependent metalloprotease. It is part of the M13 family and is expressed mainly in bone and dental tissues, including osteoblasts, osteocytes, and odontoblasts.

The PHEX protein is a type II transmembrane protein with an extracellular catalytic domain that contains the characteristic HEXXH zinc-binding motif. Its precise biological substrates are not fully established, but it is believed to regulate phosphate homeostasis by modulating the activity or levels of FGF23, a hormone produced by bone that reduces renal phosphate reabsorption and 1,25-dihydroxyvitamin D production.

Mutations in PHEX cause X-linked hypophosphatemia (XLH), a hereditary disorder characterized by renal phosphate wasting, hypophosphatemia, rickets in children, and, over time, bone deformities, short stature, and dental problems. Diagnosis is based on biochemical findings, clinical features, and genetic testing. Treatment traditionally included phosphate supplements and active vitamin D analogs; newer approaches target FGF23 signaling, such as burosumab, a monoclonal antibody against FGF23.

In research and clinical context, PHEX is recognized as a key regulator of phosphate metabolism, with its loss leading to dysregulation of mineral homeostasis and skeletal manifestations. Ongoing studies aim to clarify its substrates and mechanisms, and to optimize therapies for XLH and related disorders.