PHEX^L222P Mutation Increases Phex Expression in a New ENU Mouse Model for XLH Disease

Phex^L222P mouse is a new ENU mouse model for XLH disease due to Leu to Pro amino acid modification at position 222. Phex^L222P mouse is characterized by growth retardation, hypophosphatemia, hypocalcemia, reduced body bone length, and increased epiphyseal growth plate thickness and femur diameter despite the increase in PHEX^L222P expression. Actually, Phex^L222P mice show an increase in Fgf23, Dmp1, and Mepe and Slc34a1 (Na-Pi IIa cotransporter) mRNA expression similar to those observed in Hyp mice. Femoral osteocalcin and sclerostin and Slc34a1 do not show any significant variation in Phex^L222P mice. Molecular dynamics simulations support the experimental data. P222 might locally break the E217-Q224 β-sheet, which in turn might disrupt inter-β-sheet interactions. We can thus expect local protein misfolding, which might be responsible for the experimentally observed PHEX^L222P loss of function. This model could be a valuable addition to the existing XLH model for further comprehension of the disease occurrence and testing of new therapies.