SIADH Due to Gene Mutation in Vasopressin Receptor

The authors described 2 unrelated male infants (2.5 and 3 months of age) with clinical and biochemical evidence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) including irritability and/or seizures, hyponatremia, hypochloremia, and hypo-osmolality, with relatively increased urinary osmolalities and sodium concentrations. However, instead of measurable values of plasma ADH, concentrations of ADH were undetectable in both infants. In the absence of other causes of SIADH (neural insults, drug exposure), the investigators questioned the possibility of a constitutively active mutation in the gene (AVPR2, chromosome Xq28, OMIM 304800) encoding the vasopressin-2 receptor (V2R), a G-protein-coupled 7 transmembrane receptor (GPCR) that activates adenylyl cyclase. Sequencing of AVPR2 revealed hemizygous mutations in codon 137 (arginine) in both subjects: C770T resulting in Arg137Cys; G771T leading to Arg137Leu. Codon 137 is located in the second intracytoplasmic loop at the end of transmembrane domain III, a highly conserved region in all GPCRs. One of the asymptomatic mothers was heterozygous for the same mutation present in her son; the mutation in AVPR2 in the other patient was apparently spontaneous. Expression of the mutated V2R in COS-7 cells revealed that basal levels of cAMP generation were 4- to 7-fold greater than that of cells expressing wild-type receptor, consistent with a constitutively active V2R. The patients were treated successfully with oral urea to induce an osmotic diuresis. The authors suggested that the possibility of a gain-of-function (GOF) mutation in AVPR2 be considered in other patients without an apparent cause of SIADH and with low serum concentrations of ADH.

Editor’s Comment: The V2R now joins a number of other GPCRs with germline mutations that render them constitutively active and lead to dysfunction of the endocrine system including: LHR–familial male-limited isosexual precocity; TSHR–autosomal dominant nonimmune hyperthyroidism; CaSR – autosomal dominant hypocalcemia; MC2R–corticotropin independent hyperadrenocorticism; FSHR–familial ovarian hyperstimulation syndrome; PTH/PTHrPR–Jansen’s metaphyseal chondrodysplasia with hypercalcemia.¹ It is of great interest that in patients with nephrogenic diabetes insipidus, the substitution of histidine for arginine at codon 137 has been identified. Thus, different mutations of the same amino acid in V2R lead to functional or non-functional states, emphasizing the critical importance of this site and its effect on the receptor’s 3-dimensional configuration. It would also be of interest to assess water homeostatic mechanisms (water loading or deprivation) in the woman who is heterozygous for the GOF mutation in V2R to determine whether there is a gene dosage affect for this protein (Figure).

Physiology of Water Homeostasis in Humans (Panel A) and Pathway of AVP Signaling in Renal Collecting-Duct Cells Involved in Regulating Water Excretion (Panel B). Reprinted with permission Knoers NVAM. N Engl J Med. 2005;352:1847-1850. Copyright ©2005. Massachusetts Medical Society. All rights reserved.


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