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

J Clin Endocrinol Metab. 2019 Apr 1;104(4):1079-1089. doi: 10.1210/jc.2018-01250.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Bone and Bones / abnormalities*
  • Chromogranins / genetics*
  • DNA Mutational Analysis
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / genetics*
  • Gain of Function Mutation
  • Heterozygote
  • Humans
  • Hyponatremia / genetics*
  • Loss of Function Mutation
  • Male
  • Maternal Inheritance
  • Phenotype
  • Pseudohypoparathyroidism
  • Puberty, Precocious / genetics*


  • Chromogranins
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs