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

Carole El Hakam; Alexis Parenté; Fabienne Baraige; Laetitia Magnol; Lionel Forestier; Florent Di Meo; Véronique Blanquet

doi:10.3390/genes13081356

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

Genes (Basel). 2022 Jul 28;13(8):1356. doi: 10.3390/genes13081356.

Authors

Carole El Hakam¹, Alexis Parenté¹, Fabienne Baraige¹, Laetitia Magnol¹, Lionel Forestier¹, Florent Di Meo², Véronique Blanquet¹

Affiliations

¹ INSERM U1094, INRAE USC1501, IRD U270, EpiMaCT-Epidemiology of Chronic Diseases in Tropical Zone, Univ. Limoges, 2 Rue Pr Descottes, F-87000 Limoges, France.
² INSERM U1248 Pharmacology & Transplantation, Univ. Limoges, 2 Rue Pr Descottes, F-87000 Limoges, France.

Abstract

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.

Keywords: ENU; XLH; bone; hypophosphatemia; phex; skeletal development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone and Bones / metabolism
Disease Models, Animal
Fibroblast Growth Factors* / genetics
Mice
Mutation
PHEX Phosphate Regulating Neutral Endopeptidase / genetics*
PHEX Phosphate Regulating Neutral Endopeptidase / metabolism

Substances

Fibroblast Growth Factors
PHEX Phosphate Regulating Neutral Endopeptidase
Phex protein, mouse

Grants and funding

This project was co-financed by the European Union, the Limousin Regional Council, and the French National Institute for Agricultural Research. CEH was supported by a PhD fellowship from the Lebanese University and the Azm & Saade Association from Lebanon. AP were supported by a PhD fellowship from INRA/Region Limousin and the Foundation for Medical Research.