Il calcium sensing receptor determinante genetico dell'ipercalciuria primaria

Alterations in calcium sensing receptor (CaSR) function lead to calcium metabolism disorders. The non-conservative polymorphism Arg990Gly seems to induce a gain-of-function of the receptor that could predispose to primary hypercalciuria. The aims of this study were to confirm the increased frequency of 990Gly allele of CaSR in subjects with primary hypercalciuria, to evaluate if 990Gly allele produces a gain-of-function for CaSR in transfected HEK-293 cells and to investigate the response to calcimimetic treatments (NPS-R568). The clinical study confirmed that 990Gly allele frequency was higher in hypercalciuric subjects (8.5%) than in normocalciuric ones (1.7%, chi-square=11.5; df=1, p=0.001). The calcium urinary escretion was increased in subjects bearing 990Gly allele (7.59±0.63mmol/24h vs 5.82±0.19mmol/24h, 0=0.006). The functional study demonstrated that both CaCl2 and NPS-R568 EC50 were lower in HEK-990Gly cells in comparison with HEK-990Arg cells (respectively: 2.69±0.11mM [n=19] vs 4.49±0.28mM [n=12], p=0.0001; 0.67(0.08mM [n=15] vs 1.41(0.09mM [n=16], p=0.0001). We concluded that Arg990Gly polymorphism results in a gain-of-function for CaSR and individuals bearing 990Gly allele may be predisposed to primary hypercalciuria.