TARGETED INACTIVATION OF NPT2 IN MICE LEADS TO SEVERE RENAL PHOSPHATEWASTING, HYPERCALCIURIA, AND SKELETAL ABNORMALITIES

Npt2 encodes a renal-specific, brush-border membrane Na+-phosphate (P- i) cotransporter that is expressed in the proximal tubule where the bu lk of filtered P-i is reabsorbed. Mice deficient in the Npt2 gene mere generated by targeted mutagenesis to define the role of Npt2 in the o verall maintenance of P-i homeostasis, determine its impact on skeleta l development, and clarify its relationship to autosomal disorders of renal P-i reabsorption in humans. Homozygous mutants (Npt2(-/-)) exhib it increased urinary P-i excretion, hypophosphatemia, an appropriate e levation in the serum concentration of 1,25-dihydroxyvitamin D with at tendant hypercalcemia, hypercalciuria and decreased serum parathyroid hormone levels, and increased serum alkaline phosphatase activity. The se biochemical features are typical of patients with hereditary hypoph osphatemic rickets with hypercalciuria (HHRH), a Mendelian disorder of renal P-i reabsorption. However; unlike HHRH patients, Npt2(-/-) mice do not have rickets or osteomalacia, At weaning, Npt2(-/-) mice have poorly developed trabecular bone and retarded secondary ossification, but, with increasing age, there is a dramatic reversal and eventual ov ercompensation of the skeletal phenotype, Our findings demonstrate tha t Npt2 is a major regulator of P-i homeostasis and necessary for norma l skeletal development.