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A new multi-system disorder caused by the Gαs mutation p.F376V

Biebermann, Heike, Kleinau, Gunnar, Schnabel, Dirk, Bockenhauer, Detlef, Wilson, Louise C, Tully, Ian, Kiff, Sarah, Scheerer, Patrick, Reyes, Monica, Paisdzior, Sarah, Gregory, John W, Allgrove, Jeremy, Krude, Heiko, Mannstadt, Michael, Gardella, Thomas J, Dattani, Mehul, Jüppner, Harald and Grüters, Annette 2019. A new multi-system disorder caused by the Gαs mutation p.F376V. Journal of Clinical Endocrinology and Metabolism 104 (4) , pp. 1079-1089. 10.1210/jc.2018-01250

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Context The alpha-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, while somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright Syndrome. Objective We here report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function. Design, 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 differ from known Gαs-related diseases and suggested gain-of-function at the receptors for vasopressin (V2R) and lutropin (LHCGR), yet increased serum parathyroid hormone (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 multi-system disorder.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Endocrine Society
ISSN: 0021-972X
Date of First Compliant Deposit: 25 October 2018
Date of Acceptance: 8 October 2018
Last Modified: 21 May 2022 21:36

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