NEW YORK (Reuters Health) - In patients with urolithiasis or bone demineralization, heterozygous mutations in the NPT2a gene may cause hypophosphatemia and urinary phosphate loss, French researchers report in the September 26th issue of The New England Journal of Medicine.

Dr. Dominique Prié from the Hôpital Bichat, Paris, and colleagues studied 20 patients with urolithiasis or bone demineralization. These patients also had persistent idiopathic hypophosphatemia and a decrease in maximal renal phosphate reabsorption. The French team sequenced the coding region of the gene for NPT2a in all of these patients.

Of the 20 patients, one patient with urolithiasis and one with bone demineralization were heterozygous for two distinct mutations, the researchers found. In one patient, the mutation consisted of a substitution of phenylalanine for alanine at position 48. The other mutation was a substitution of methionine for valine at position 147.

In oocytes that expressed the mutant NPT2a, phosphate-induced current and sodium-dependent phosphate uptake were impaired, the researchers note. "Coinjection of oocytes with wild-type and mutant RNA indicated that the mutant protein had altered function," they add.

"Our study provides genetic evidence that heterozygous NPT2a mutations are involved in hypophosphatemia resulting from idiopathic renal phosphate loss and indicates that NPT2a plays a major part in phosphate homeostasis," Dr. Prié and colleagues conclude.

"The identification of functional variants of the NPT2a gene in patients with hypophosphatemia associated with urolithiasis or bone demineralization also provides genetic evidence that a defect in renal phosphate reabsorption may contribute to the pathogenesis of these two common disorders," they add.

"This work is important because it links the extensive literature on animal and cellular models of NPT2a to human physiology," Dr. Henry M. Kronenberg from Massachusetts General Hospital, Boston, comments in a journal editorial.

"Furthermore, it shows that mutations in NPT2a can contribute to nephrolithiasis and low bone mass in humans and suggests that changes in NPT2a levels may also cause other human diseases," he adds.

N Engl J Med 2002;347:983-991,1022-1024.

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