Mutational analysis of PHEX gene in X-linked hypophosphatemia

Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.31). 10/1998; 83(10):3615-23. DOI: 10.1210/jcem.83.10.5180
Source: PubMed

ABSTRACT Hypophosphatemic rickets is commonly an X-linked dominant disorder (XLH or HYP) associated with a renal tubular defect in phosphate transport and bone deformities. The XLH gene, referred to as PHEX, or formerly as PEX (phosphate regulating gene with homologies to endopeptidases on the X-chromosome), encodes a 749-amino acid protein that putatively consists of an intracellular, transmembrane, and extracellular domain. PHEX mutations have been observed in XLH patients, and we have undertaken studies to characterize such mutations in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH by single stranded conformational polymorphism and DNA sequence analysis. We identified 31 mutations (7 nonsense, 6 deletions, 2 deletional insertions, 1 duplication, 2 insertions, 4 splice site, 8 missense, and 1 within the 5' untranslated region), of which 30 were scattered throughout the putative extracellular domain, together with 6 polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Single stranded conformational polymorphism was found to detect more than 60% of these mutations. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The unique point mutation (a-->g) of the 5'untranslated region together with the other mutations indicates that the dominant XLH phenotype is unlikely to be explained by haplo-insufficiency or a dominant negative effect.

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Available from: Peter Hendy Dixon, May 07, 2014
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    • "To study such interactions between alteration of bone matrix quality in metabolic bone disorders with in vivo force distributions and tissue growth, we selected rickets, which is associated with decreased mineralisation due to deficiency of vitamin D, phosphorus or calcium [13]. This impaired mineralisation has been shown to alter the bone material quality and the functional biomechanics of the tissue at micro-[14] and nanoscale levels [15]. "
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    ABSTRACT: Metabolic bone disorders such as rickets are associated with altered in vivo muscular force distributions on the skeletal system. During development, these altered forces can potentially affect the spatial and temporal dynamics of mineralised tissue formation, but the exact mechanisms are not known. Here we have used a murine model of hypophosphatemic rickets (Hpr) to study the development of the mineralised nanostructure in the intramembranously ossifying scapulae (shoulder bone). Using position-resolved scanning small angle X-ray scattering (SAXS), we quantified the degree and direction of mineral nanocrystallite alignment over the width of the scapulae, from the load bearing lateral border (LB) regions to the intermediate infraspinous fossa (IF) tissue. These measurements revealed a significant (p<0.05) increase in mineral nanocrystallite alignment in the LB when compared to the IF region, with increased tissue maturation in wild-type mice; this was absent in mice with rickets. The crystallites were more closely aligned to the macroscopic bone boundary in the LB when compared to the IF region in both wild type and Hpr mice, but the degree of alignment was reduced in Hpr mice. These findings are consistent with a correlation between the nanocrystallites within fibrils and in vivo muscular forces. Thus our results indicate a relevant mechanism for the observed increased macroscopic deformability in rickets, via a significant alteration in the mineral particle alignment, which is mediated by an altered spatial distribution of muscle forces.
    Bone 05/2012; 51(3):553-62. DOI:10.1016/j.bone.2012.04.021 · 4.46 Impact Factor
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    • "There are several mutations associated with PHEX-hypophosphatemia (see the PHEX mutation database: and most of the mutations are located in the region encoding the extracellular domain, but there are also examples of pathological mutations in the 5'UTR (Dixon, Christie et al. 1998) and 3'UTR (Ichikawa, Traxler et al. 2008) of the gene. Fig. 1. "
    Contemporary Aspects of Endocrinology, 11/2011; , ISBN: 978-953-307-357-6
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    • "In addition, several XLH patients have been shown to have enamel defects (Goodman et al., 1998). Previously, many types of loss-of-function mutations in PHEX (phosphate regulating gene homologies to endopeptidase on the X chromosome) were reported in XLH patients (The Hyp Consortium, 1995; Dixon et al., 1998). The Hyp mouse is a murine homolog of human XLH and has been used as an animal model for human XLH rickets (Eicher et al., 1976; Tenenhouse et al., 1978), while the Phex gene in Hyp mice has a deletion of the 3Ј end (Beck et al., 1997; Strom et al., 1997). "
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    ABSTRACT: Hyp mice (murine homologue of human X-linked hypophosphatemia) have a disorder in phosphate homeostasis, and display hypomineralization in bones and teeth. We investigated whether a mutation of Phex (phosphate regulating gene homologies to endopeptidase on the X chromosome) has an effect on the expression level of type II sodium-dependent phosphate co-transporter (Npt2) in the developing teeth of the Hyp mouse. Quantitative RT-PCR analyses revealed that the amount of Npt2b mRNA, an isoform of Npt2, in Hyp mouse tooth germs was significantly lower than that in wild-type mice, in both in vivo and in vitro experiments. In addition, tooth germs from wild-type mice cultured in medium supplemented with antisense oligo-deoxynucleotide for Phex also showed a reduction of Npt2b mRNA expression. These findings suggest that the loss of Phex function is related to the defect of Npt2b expression in teeth, and Npt2b reduction is an intrinsic defect of Hyp murine teeth.
    Journal of Dental Research 03/2007; 86(2):158-62. DOI:10.1177/154405910708600210 · 4.14 Impact Factor
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