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.

• Authors: Heike Biebermann, Gunnar Kleinau, Dirk Schnabel, Detlef Bockenhauer, Louise C Wilson, Ian Tully, Sarah Kiff, Patrick Scheerer, Monica Reyes, Sarah Paisdzior, John W Gregory, Jeremy Allgrove, Heiko Krude, Michael Mannstadt, Thomas J Gardella, Mehul Dattani, Harald Jüppner, Annette Grüters
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 104 Issue 4 Pg. 1079-1089 (04 01 2019) ISSN: 1945-7197 [Electronic] United States
• PMID: 30312418 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Endocrine Society.

Chemical References

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

Topics

• 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)