Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets
ABSTRACT X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related gene with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH.
We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously.
Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A>T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T>C in exon 22, resulting in p.F731S.
We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH.
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ABSTRACT: Abstract Familial hypophosphatemic rickets (HR), the most common inherited form of rickets, is a group of inherited renal phosphate wasting disorders characterized by growth retardation, rickets with bone deformities, osteomalacia, poor dental development, and hypophosphatemia. The purpose of this study was to identify the genetic defect responsible for familial HR in a 4-generation Chinese Han pedigree by exome sequencing and Sanger sequencing. Clinical features include skeletal deformities, teeth abnormalities, hearing impairments and variable serum phosphate level in patients of this family. A novel deletion mutation, c.1553delT (p.F518Sfs*4), was identified in the X-linked phosphate regulating endopeptidase homolog gene (PHEX). The mutation is predicted to result in prematurely truncated and loss-of-function PHEX protein. Our data suggest that exome sequencing is a powerful tool to discover mutation(s) in HR, a disorder with genetic and clinical heterogeneity. The findings may also provide new insights into the cause and diagnosis of HR, and have implications for genetic counseling and clinical management.Biological Chemistry 07/2014; 396(1). DOI:10.1515/hsz-2014-0187 · 2.69 Impact Factor
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ABSTRACT: X-Linked hypophosphatemic rickets (HYP, XLH) is a disorder of phosphate homeostasis, characterized by renal phosphate wasting and hypophosphatemia, with normal to low 1,25-dihydroxy vitamin D3 serum levels. The purpose of our study was the detection of inactivating mutations in the PHEX gene, the key enzyme in the pathogenesis of XLH. The 16 patients, representing eight families, presented with suspected XLH from biochemical and clinical evidence. All 16 were referred for mutational analysis of the PHEX gene. We detected three novel disease-causing mutations, C59S, Q394X, and W602, for which a loss of function can be predicted. A G28S variation, found in two healthy probands, may be a rare polymorphism. Another mutation, A363 V, is localized on the same allele as the C59S mutation, thus its functional consequences cannot be proven. Furthermore, we detected a deletion of three nucleotides in exon 15 which resulted in the loss of amino acid threonine 535. Heterozygosity of this mutation in a male patient without any chromosomal aberrations suggests its presence as a mosaic. Novel large deletions were detected using multiplex ligation-dependent probe amplification (MLPA) analysis. Two of these deletions, loss of exon 22 alone or exons 21 and 22 together, may result in the translation of a C-terminal truncated protein. Two large deletions comprise exons 1-9 and exons 4-20, respectively, and presumably result in a nonfunctional protein. We conclude that molecular genetic analysis confirms the clinical diagnosis of XLH and should include sequence analysis as well as the search for large deletions, which is facilitated by MLPA.Calcified Tissue International 07/2009; 85(3):211-20. DOI:10.1007/s00223-009-9260-8 · 2.75 Impact Factor
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ABSTRACT: X-linked hypophosphatemia (XLH) is characterized by renal phosphate wasting with hypophosphatemia, short stature, and rachitic manifestations. We describe a novel nonsense mutation in exon 3 of the PHEX gene (Glu(96)X (c.286G>T) causing XLH in a mother and daughter of Indian ancestry. The mother was noted to have concomitant vitamin D insufficiency. Our report identifies a novel nonsense mutation in the PHEX gene causing XLH. It also highlights the fact that the presence of concomitant vitamin D insufficiency should not preclude the diagnosis of familial forms of hypophosphatemic rickets, especially if more than one family member is affected.Nephron Physiology 01/2010; 116(3):p17-21. DOI:10.1159/000319318 · 1.55 Impact Factor