Persistent elevation of urine aquaporin-2 during water loading in a child with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) caused by a R137L mutation in the V2 vasopressin receptor

Normal fluid balance requires an intact thirst mechanism and normal free water excretion by the kidneys, mediated by arginine vasopressin (AVP), also known as antidiuretic hormone (ADH). AVP exerts its antidiuretic action via the V2 vasopressin receptor (V2R) in the basolateral membrane of renal collecting duct cells. Binding and activation of the V2R, a G-protein coupled receptor (GPCR), increases intracellular cAMP and mediates shuttling of the water channel aquaporin-2 (AQP2) from cytosolic storage vesicles to the apical membrane of collecting duct cells, resulting in increased water permeability and antidiuresis [1]. A fraction of this AQP2 is excreted in the urine and has been found to be a useful marker of V2R activity [2]. Water loading in a normal individual suppresses plasma AVP levels and attenuates antidiuresis as a result of decreased AQP2 shuttling to the apical membrane of collecting duct cells. Consequently, less AQP2 is shed into the urine [3,4].We have previously described a novel syndrome of impaired water excretion mediated by gain-of-function mutations in the X-linked gene for V2R in two unrelated male infants who presented with irritability or seizures and hyponatremia [5]. Their clinical and laboratory findings were consistent with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) yet their AVP levels were undetectable. We have termed this condition "nephrogenic syndrome of inappropriate antidiuresis" (NSIAD). Each patient carries a missense mutation in codon 137 of AVPR2, which results in a change from arginine to cysteine (R137C) in one patient and to leucine (R137L) in the other [5]. Codon 137 is part of a highly conserved DRY/H motif located at the junction of the third transmembrane domain and the second intracellular loop of class 1 GPCRs. This motif is critical for G-protein coupling [6] and the two mutations each resulted in a constitutively active V2R [5].Since our initial description of NSIAD, many reports from a