Hereditary hypophosphatemic pickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a renal pho sphate (Pi) wasting disease first described in an extended Bedouin kindred, is characterized by hypophosphatemia, elevated serum 1,25-dihydroxyvitamin D levels, hypercalciuria, rickets, and osteomalacia. Correction of all abn ormalities, except for renal Pi wasting, can be achieved by oral Pi supplem entation. These findings and the demonstration that mice that are homozygou s for the disrupted Na/Pi cotransporter gene Npt2 exhibit many of the bioch emical features of HHRH suggested that mutations in the human ortho-logue N PT2 might be responsible for HHRH. The NPT2 gene in affected individuals fr om the Bedouin kindred and four small families was screened for mutations t o test this hypothesis. No putative disease-causing mutation was found. Two single nucleotide polymorphisms (SNP), a silent substitution in exon 7 and a nucleotide substitution in intron 4, were identified, and neither consis tently segregated with HHRH in the Bedouin kindred. Linkage analysis indica ted that the two NPT2 intragenic SNP as well as five microsatellite markers in the NPT2 gene region were not linked to HHRH in the Bedouin kindred. Th erefore, this is evidence to exclude NPT2 as a candidate gene for HHRH in t he families that were studied.