Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis

Abstract

Nephrogenic syndrome of inappropriate diuresis is a recently-discovered rare disease caused by gain-of-function mutations of the V2 vasopressin receptor gene, AVPR2. To date, mutations of Phe229 and Arg137 have been identified as gain-of-function mutations in V2 vasopressin receptor (V2R). The mutant receptors lead to hyponatremia, which may lead to clinical symptoms in infants. In this study, we present a newly-identified Ile130Asn (I130N) substitution, causing NSIAD in a family. Characterization of the mutation revealed basal constitutive activity of V2R. We have demonstrated that the I130N mutation results in constitutive cAMP generation in HEK293 cells. Basal activity of the mutant receptor could be blocked by the inverse agonist tolvaptan and arginine-vasopressin stimulation enhanced the cAMP production of I130N-V2R. The mutation causes a biased receptor conformation since the basal cAMP generation activity of I130N does not lead to interaction with β-arrestin. The constitutive activity of the mutant receptor causes constitutive dynamindependent and β-arrestin-independent internalization. The inhibition of the basal internalization using dominant-negative dynamin resulted in an increased cell surface expression. In contrast to the constitutive internalization, agonist-induced endocytosis was β-arrestin dependent. Based on our findings, tolvaptan could be used for treatment of hyponatremia, shown in patients with nephrogenic syndrome of inappropriate diuresis who carry the I130N-V2R mutation.

Universal activation mechanism of class A GPCRs

“…The functional consequence of these single point mutations can be rationalized by analysing if they are stabilizing/destabilizing the contacts in the universal activation pathway or promoting/retarding the required helix movement upon activation (Figure 7b and Figure 7—figure supplement 1). For example, I130 3×43 N/F (in layer 2 of the universal activation pathway) in V2R was reported as a gain-/loss-of-function mutation that causes nephrogenic syndrome of inappropriate antidiuresis 40 or nephrogenic diabetes insipidus 41 , respectively. I130 3×43 N/F likely loosens/stabilizes the hydrophobic lock, weakens/strengthens the TM3-TM6 packing and leads to constitutively active/inactive receptors.…”

Identification of a Novel Arginine Vasopressin Receptor 2 Mutation (p.V183M) in a Chinese Family with Nephrogenic Diabetes Insipidus

“…By binding AVPR2, AVP can activate Gs/adenylate cyclase and then regulate the water channel AQP2 in renal tubules and collecting ducts, and finally the concentration of urine [Caletti et al, 2014]. In this process, loss of AVPR2 function may induce a function disorder of the renal tubules and collecting ducts and thus break the water balance of the body [Erdelyi et al, 2015].…”

Nephrogenic syndrome of inappropriate antidiuresis secondary to an activating mutation in the arginine vasopressin receptor AVPR2

“…To date, fewer than 30 cases of NSIAD due to activating AVPR2 mutations have been reported ,. While the majority of affected individuals harbour mutations at codon 137, activating mutations affecting other amino acids (p.Phe299Val and p.Ile130Asn) have also been described . It is interesting to note the marked heterogeneity with respect to age at diagnosis and severity of the disorder between subjects.…”

“…10,[23][24][25][26][27][28][29][30][31][32] While the majority of affected individuals harbour mutations at codon 137, activating mutations affecting other amino acids (p.Phe299Val and p.Ile130Asn) have also been described. 22,33 It is interesting to note the marked heterogeneity with respect to age at diagnosis and severity of the disorder between subjects. For example, several probands presented with neonatal seizures in the context of hyponatraemia but, on screening family members, causative mutations and abnormal water load test dynamics were also observed in otherwise apparently unaffected individuals.…”