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Mutational Analysis of PHEX Gene in X-Linked Hypophosphatemia¹

Medical Research Council Molecular Endocrinology Group, Medical Research Council Clinical Sciences Centre (P.H.D., P.T.C., C.W., D.T., R.V.T.), Imperial College School of Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom; Renal Division (M.G.), Department of Molecular Microbiology and Center for Genetics in Medicine (D.S.), and Metabolic Research Unit, Shriners Hospital for Children and Division of Bone and Mineral Diseases (M.P.W.) ,Washington University School of Medicine (M.G.), St. Louis, Missouri 63110; Division of Genetics, Children’s Hospital (I.H.), Boston, Massachusetts 02115; Serono Laboratories, Inc. (J.M.G.), Norwell, Massachusetts 02061; Medizinische Hochschule Hannover, Abteilung Humangenetik, Zentrum Kinderheilkunde und Humangenetik (J.S.), Hannover D-30625, Germany; Childrens Medical Center of Brooklyn, Kings County Hospital Centre, University Hospital of Brooklyn (B.S.), Brooklyn, New York 11203-2098; Department of Growth and Endocrinology, The Birmingham Children’s Hospital National Health Service Trust (N.S.), Ladywood, Birmingham B16 8ET, United Kingdom; Alder Hey Children’s Hospital (C.S.), Liverpool, L12 2AR, United Kingdom; and Hospital de Pediatria Garrahan, Laboratoria de Metabolismo Calccio y Oseo, Endocrinologia (C.T.), Buenos Aeres, Argentina.

Address all correspondence and requests for reprints to: R. V. Thakker, Medical Research Council Molecular Endocrinology Group, Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom. E-mail: rthakker{at}rpms.ac.uk

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 (ag) 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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