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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; Grüters, Annette

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

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  • Media type: E-Article
  • Title: A New Multisystem Disorder Caused by the Gαs Mutation p.F376V
  • Contributor: 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; Grüters, Annette
  • Published: The Endocrine Society, 2019
  • Published in: The Journal of Clinical Endocrinology & Metabolism, 104 (2019) 4, Seite 1079-1089
  • Language: English
  • DOI: 10.1210/jc.2018-01250
  • ISSN: 0021-972X; 1945-7197
  • Keywords: Biochemistry (medical) ; Clinical Biochemistry ; Endocrinology ; Biochemistry ; Endocrinology, Diabetes and Metabolism
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Context</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective</jats:title> <jats:p>We report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function.</jats:p> </jats:sec> <jats:sec> <jats:title>Design and Setting</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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&amp;gt;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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The Gαs p.F376V mutation causes a previously unrecognized multisystem disorder.</jats:p> </jats:sec>
  • Access State: Open Access