title: A novel Phex mutation in a new mouse model of hypophosphatemic rickets.
abstract: X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disease characterized by renal phosphate wasting, aberrant vitamin D metabolism, and defective bone mineralization. It is known that XLH in humans and in certain mouse models is caused by inactivating mutations in PHEX/Phex (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). By a genome-wide N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a dominant mouse mutation that exhibits the classic clinical manifestations of XLH, including growth retardation, skeletal abnormalities (rickets/osteomalacia), hypophosphatemia, and increased serum alkaline phosphatase (ALP) levels. Mapping and sequencing revealed that these mice carry a point mutation in exon 14 of the Phex gene that introduces a stop codon at amino acid 496 of the coding sequence (Phex(Jrt) also published as Phex(K496X) [Ichikawa et al., 2012]). Fgf23 mRNA expression as well as that of osteocalcin, bone sialoprotein, and matrix extracellular phosphoglycoprotein was upregulated in male mutant long bone, but that of sclerostin was unaffected. Although Phex mRNA is expressed in bone from mutant hemizygous male mice (Phex(Jrt)/Y mice), no Phex protein was detected in immunoblots of femoral bone protein. Stromal cultures from mutant bone marrow were indistinguishable from those of wild-type mice with respect to differentiation and mineralization. The ability of Phex(Jrt)/Y osteoblasts to mineralize and the altered expression levels of matrix proteins compared with the well-studied Hyp mice makes it a unique model with which to further explore the clinical manifestations of XLH and its link to FGF23 as well as to evaluate potential new therapeutic strategies.
authors.affiliation: Centre For Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Celeste
authors.initials: C
authors.lastname: Owen
authors.forename: Frieda
authors.initials: F
authors.lastname: Chen
authors.forename: Ann M
authors.initials: AM
authors.lastname: Flenniken
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Osborne
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.forename: S Lee
authors.initials: SL
authors.lastname: Adamson
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: Jane E
authors.initials: JE
authors.lastname: Aubin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002113:Calcification, Physiologic / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005038:Ethylnitrosourea; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D000089703:Fibroblast Growth Factor-23; D040181:Genetic Diseases, X-Linked; D006023:Glycoproteins / Q000096:biosynthesis; D058574:Integrin-Binding Sialoprotein / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D015675:Osteocalcin / Q000096:biosynthesis; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics*; D010750:Phosphoproteins / Q000096:biosynthesis; D017354:Point Mutation; D012333:RNA, Messenger / Q000096:biosynthesis; D017422:Sequence Analysis, DNA; D017154:Stromal Cells
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D006023:Glycoproteins; D058574:Integrin-Binding Sialoprotein; D036341:Intercellular Signaling Peptides and Proteins; D009153:Mutagens; D010750:Phosphoproteins; D012333:RNA, Messenger; C486030:Sost protein, mouse; D015675:Osteocalcin; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse; D005038:Ethylnitrosourea