Heterozygous mutations in the NPT2a gene may be responsible for hypophosphatemia and urinary phosphate loss in persons with urolithiasis or bone demineralization.

Renal ammonium (NH 3 ؉ NH 4 ؉ ) transport is a key process for body acid-base balance. It is well known that several ionic transport systems allow NH 4 ؉ transmembrane translocation without high specificity for NH 4 ؉ , but it is still debated whether NH 3 , and more generally, gas, may be transported by transmembrane proteins.

Impaired renal phosphate reabsorption, as measured by dividing the tubular maximal reabsorption of phosphate by the glomerular filtration rate (TmP/GFR), increases the risks of nephrolithiasis and bone demineralization. Data from animal models suggest that sodium-hydrogen exchanger regulatory factor 1 (NHERF1) controls renal phosphate transport. We sequenced the NHERF1 gene in 158 patients, 94 of whom had either nephrolithiasis or bone demineralization. We identified three distinct mutations in seven patients with a low TmP/GFR value. No patients with normal TmP/GFR values had mutations. The mutants expressed in cultured renal cells increased the generation of cyclic AMP (cAMP) by parathyroid hormone (PTH) and inhibited phosphate transport. These NHERF1 mutations suggest a previously unrecognized cause of renal phosphate loss in humans.