PHEXL222P Mutation Increases Phex Expression in a New ENU Mouse Model for XLH Disease

Abstract

PhexL222P mouse is a new ENU mouse model for XLH disease due to Leu to Pro amino acid modification at position 222. PhexL222P 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 PHEXL222P expression. Actually, PhexL222P 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 PhexL222P 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 PHEXL222P 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.

The contribution of a novel PHEX gene mutation to X-linked hypophosphatemic rickets: a case report and an analysis of the gene mutation dosage effect in a rat model

“…Studies have indicated that a new mouse model for XLH disease, induced by N-ethyl-N-nitrosourea (ENU) and carrying the PHEX L222P mutation, exhibits an overexpression of PHEX transcript and protein, resulting in a loss-of-function phenotype ( 21 ). However, our findings in the mutant (c.1985delA) rat model revealed reduced expression of PHEX mRNA.…”

De Novo Large Deletions in the PHEX Gene Caused X-Linked Hypophosphataemic Rickets in Two Italian Female Infants Successfully Treated with Burosumab

“…It contains 22 exons and encodes the phosphate-regulating neutral endopeptidase PHEX, a glycoprotein of 749 amino acids (NP_000435.3) that belongs to the type II integral membrane zinc-dependent endopeptidase family. The PHEX protein has a large extracellular C-terminal domain, which contains the active sites and glycosylation sites, a transmembrane domain, and an N-terminal cytoplasmic tail [26,27]. It is predominantly expressed in osteoblasts, osteocytes, cartilage, and odontoblasts, and in these cells, PHEX deficiencies impair the cellular trafficking, endopeptidase activity, and FGF23 signaling that, in turn, reduce renal phosphate reabsorption, resulting in abnormal bone mineralization and hypophosphatemia [7].…”