Mutational Analysis of PHEX Gene in X-Linked Hypophosphatemia 1

Division of Bone and Mineral Diseases, Washington University in St. Louis, San Luis, Missouri, United States
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 10/1998; 83(10):3615-23. DOI: 10.1210/jcem.83.10.5180
Source: PubMed


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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    • "A large number of mutations occur randomly across mainly the extracellular domain, which is encoded by exons2-22, but a mutation in the 3'-untranslated region has also recently been identified2). Moreover, the frequency of de novo mutations has been estimated to be approximately 20%11,12,13). These findings suggest that the PHEX gene appears to be particularly prone to mutations for unknown reasons13). "
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    ABSTRACT: X-linked hypophosphatemia (XLH) is the most common form of familial hypophosphatemic rickets and it is caused by loss-of-function mutations in the PHEX gene. Recently, a wide variety of PHEX gene defects in XLH have been revealed; these include missense mutations, nonsense mutations, splice site mutations, insertions, and deletions. Recently, we encountered a 2-year-9-month-old female with sporadic hypophosphatemic rickets. She underwent osteotomy, dental abscess was evident, and there was severe bowing of the legs. A low serum phosphorus level in combination with elevated serum alkaline phosphatase activity and normal serum calcium is suggestive of hypophosphatemic rickets. PHEX gene analysis revealed a splice acceptor site mutation, c.934-1G>T (IVS8(-1)G>T), at the intron8 and exon9 junction. To the best of our knowledge, this mutation is novel and has not been reported. The results of this study expand and improve our understanding of the clinical and molecular characteristics and the global pool of patients with sporadic hypophosphatemic rickets.
    Full-text · Article · Mar 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.
    Full-text · Article · May 2012 · Bone
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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. "

    Full-text · Chapter · Nov 2011
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