Hyponatremia is a common pathological condition stemming either from salt loss or from dilution.Dilution hyponatremia results from an excess water intake and/or inappropriate water reabsorption by the kidney.Inappropriate water reabsorption by the kidney (SIAD=syndrome of inappropriate antidiuresis) may be due to inappropriate vasopressin secretion or a purely renal defect (NSIAD=Nephrogenic SIAD).While uncontrolled secretion of vasopressin is most often associated with tumor cells, molecular mechanisms of NSIAD have only recently been unraveled at the molecular level.The first mechanism proposed from in vitro experiments showed the possible existence of activating mutations of the vasopressin type 2 receptor.Indeed in 2005, Feldmann and co-workers described fort the first time the cases of two neonates presenting with severe hyponatremia induced comitiality and bearing de novo mutations in the codon 136 of the gene coding for the type 2 receptor of vasopressin (V2R, on the X chromosome) leading to permanent activation of cAMP production.Several isolated reports appeared in the literature while we had the opportunity to diagnose such a case in a 2 years old child and investigate the family over three generations.A family with several probands was published by the group of Decaux et al in Belgium.We could demonstrate that the defect in the receptor function in these patients involved the overactivation of the V2R pathway up to the expression of Aquaporin 2, the final effector of water reabosrption.Moreover we showed that the heterozygous women (V2R is on the X chromosome)displayed altered responses at even mild water loads, and that patients with the mutation and altered ability to excrete free water could be completely free of hyponatremic episodes, indicating the existence of large variations in the clinical consequences of the mutation, but the permanence of the defect which is probably compensated by a very low spontaneous water intake of these patients as well maintained desensitization of the mutated V2R, which is moderately activated, insensitive to vasopressin and other agonist, antagonists or inverse agonist.In conclusion, our data combined with those from the literature suggest that the presence of activating mutations of the V2R may be more frequent than expected from the sporadic cases described and their presence even in the heterozygous state may be an aggravating factor for severe hyponatremia in face of even moderate salt loss or loss of control of water intake.