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A New Multisystem Disorder Caused by the Gas Mutation p.F376V
Ist Teil von
The journal of clinical endocrinology and metabolism, 2019-04, Vol.104 (5), p.1079
Ort / Verlag
Oxford University Press
Erscheinungsjahr
2019
Link zum Volltext
Quelle
Oxford Journals 2020 Medicine
Beschreibungen/Notizen
Context: The a subunit of the stimulatory G protein (Gas) links numerous receptors to adenylyl cyclase. Gas, 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 Gas function. Design and Setting: Clinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant Gas 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 Gas-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 Gas-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 [alpha]5 helix of G[alpha]s that are relevant for interaction with GPCRs and signal transduction. Conclusions: The Gas p.F376V mutation causes a previously unrecognized multisystem disorder. (J Clin Endocrinol Metab 104: 1079-1089, 2019)