A New Multisystem Disorder Caused by the Gαs Mutation p.F376V

Abstract

Context The α subunit of the stimulatory G protein (Gαs) links numerous receptors to adenylyl cyclase. Gαs, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, whereas somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright syndrome. Objective We report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function. Design and Setting Clinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant Gαs were determined in the presence of different G protein–coupled receptors (GPCRs) under basal and agonist-stimulated conditions. Results Both unrelated patients presented with unexplained hyponatremia in infancy, followed by severe early onset gonadotrophin-independent precocious puberty and skeletal abnormalities. An identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele in both patients; this resulted in a clinical phenotype that differed from known Gαs-related diseases and suggested gain of function at the vasopressin 2 receptor (V2R) and lutropin/choriogonadotropin receptor (LHCGR), yet increased serum PTH concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function. In vitro studies demonstrated that Gαs-F376V enhanced ligand-independent signaling at the PTH1R, LHCGR, and V2R and, at the same time, blunted ligand-dependent responses. Structural homology modeling suggested mutation-induced modifications at the C-terminal α5 helix of Gαs that are relevant for interaction with GPCRs and signal transduction. Conclusions The Gαs p.F376V mutation causes a previously unrecognized multisystem disorder.

Copeptin and its role in the diagnosis of diabetes insipidus and the syndrome of inappropriate antidiuresis

“…Finally, the forth osmoregulatory SIAD subtype (“subtype D”)—characterized by low or undetectable AVP/copeptin values—may be linked to the nephrogenic syndrome of inappropriate antidiuresis, although in the study of Fenske et al no gene alteration could be found in the respective patients. This rare syndrome is caused by x‐linked recessive gain of function variants in the AVPR2 gene, which encodes the vasopressin V2 receptor or as recently suggested also by a mutation in the GNAS gene . In affected male and female patients, the continuous activation of the vasopressin receptor leads to AVP‐independent antidiureses.…”

“…In affected male and female patients, the continuous activation of the vasopressin receptor leads to AVP‐independent antidiureses. Consecutively, AVP/copeptin levels are low or suppressed in these patients . Management of this disorder includes fluid restriction and avoidance of potential episodes of fluid overload.…”

GNAS: A New Nephrogenic Cause of Inappropriate Antidiuresis

“…The patients with the spontaneous mutation both presented with hyponatremia in the neonatal period. 4 One of these was investigated in more detail at the age of three years. Treatment until then had consisted of salt supplementation which was associated with hypertension, consistent with the concept that hyponatremia was due to water overload, rather than salt deficiency.…”

Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis

“…Recently, Biebermann et al 36 have identified an identical de novo GNAS-Gsa p.F376V variant on the maternally derived alleles of two unrelated boys with clinical features suggestive of both GOF and LOF functions of GNAS-Gsa, including NSIAD, gonadotropin-independent precocious puberty, skeletal dysplasia, and PTH resistance in the proximal but not distal tubules. In vitro studies for the p.F376V-Gsa showed enhanced ligand-independent AVPR2, LHCGR, and PTH1R signaling and blunted ligand-dependent responses.…”

“…The development of NSIAD in the two boys would provide additional support for the notion that relatively mild GOF variants of GNAS-Gsa permit survival and cause NSIAD when present in the collecting duct. Furthermore, the presence of the NSIAD-causing p.F376V variant on the maternally inherited allele may raise the possibility that the maternal transmission of the p.F68_G70del and p.M255V variants is not necessarily coincidental but has some specific effects on the water metabolism via a signal from tissues with maternal GNAS-Gsa expression as implicated by Biebermann et al 36 In summary, this study shows for the first time that germline-derived GNAS-Gsa GOF variants do exist and cause NSIAD as the salient phenotype. This study establishes a novel Gsa-mediated genetic disease and provides critical information on Gsa-mediated signal transductions.…”