Recognising that NPT2 is the major Na/Pi cotransporter in the kidney, that hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by a renal Pi leak and, that Npt2 knockout mice demonstrate a biochemical phenotype similar to that of patients with HHRH, we sought to determine whether NPT2 was a candidate gene for this disorder. Using single-strand conformation polymorphsim (SSCP) analysis and sequencing in six unrelated pedigrees with the disease, we found no disease-causing mutations. Two polymorphisms were identified in the gene and used as markers to examine segregation of NPT2 with the disease. HHRH did not segregate with the gene markers. In addition, the impact of NPT2 on bone mineral density (BMD) was examined by genotyping a population of 104 individuals for which BMD data was available, and determining whether there was an association between NPT2 genotype and bone density. No significant association was found between NPT2 genotype and BMD.

Mice homozygous for the disrupted renal type 11a sodium/phosphate (Na/Pi) cotransporter gene, Npt2, (Npt2 KO) exhibit renal Pi wasting and hypercalciuria, predisposing factors for renal stone formation. We observed that Npt2 KO mice, but not wild-type littermates form renal stones. The renal stones were evident in newborn, weanling and adult mice and composed of calcium (Ca) and Pi. The presence of renal calcification correlated with the absence of Npt2 gene expression and the presence of genes responsible for the synthesis (1alpha-hydroxylase) and catabolism (24-hydroxylase) of 1,25-dihydroxyvitamin D, whose elevated levels contribute to the hypercalciuria and renal calcification in Npt2 KO mice. The renal calcification was associated with increased osteopontin (OPN) mRNA expression and colocalized with OPN, the latter associates with renal stones in vivo and inhibits Ca mineralization in vitro). These data demonstrate that hyperphosphaturia and hypercalciuria, secondary to Npt2 gene disruption, are sufficient for the development of renal calcification.

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