MUTATIONAL ANALYSIS OF PHEX GENE IN X-LINKED HYPOPHOSPHATEMIA

Hypophosphatemic rickets is commonly an X-linked dominant disorder (XL H or HYP) associated with a renal tubular defect in phosphate transpor t and bone deformities. The XLH gene, referred to as PHEX, or formerly as PEX (phosphate regulating gene with homologies to endopeptidases o n 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 undert aken studies to characterize such mutations in 46 unrelated XLH kindre ds and 22 unrelated patients with nonfamilial XLH by single stranded c onformational polymorphism and DNA sequence analysis. We identified 31 mutations (7 nonsense, 6 deletions, 2 deletional insertions, 1 duplic ation, 2 insertions, 4 splice site, 8 missense, and 1 within the 5' un translated region), of which 30 were scattered throughout the putative extracellular domain, together with 6 polymorphisms that had heterozy gosity frequencies ranging from less than 1% to 43%. Single stranded c onformational polymorphism was found to detect more than 60% of these mutations. Over 20% of the mutations were observed in non familial XLH patients, who represented de novo occurrences of PHEX mutations. The unique point mutation (a-->g) of the 5' untranslated region together w ith the other mutations indicates that the dominant XLH phenotype is u nlikely to be explained by haplo-insufficiency or a dominant negative effect.