苯丙氨酸
低磷血症性佝偻病
低磷血症
内分泌学
内科学
生物
佝偻病
骨软化症
成纤维细胞生长因子23
骨钙素
突变体
骨桥蛋白
分子生物学
遗传学
碱性磷酸酶
维生素D与神经学
基因
甲状旁腺激素
生物化学
医学
钙
酶
作者
Celeste Owen,Frieda Chen,Ann M. Flenniken,Lucy R. Osborne,Shoji Ichikawa,S. Lee Adamson,Janet Rossant,Jane E. Aubin
摘要
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 (PhexJrt also published as PhexK496X [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 (PhexJrt/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 PhexJrt/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. J. Cell. Biochem. 113: 2432–2441, 2012. © 2012 Wiley Periodicals, Inc.
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