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J Clin Endocrinol Metab. 2018 Oct 11. doi: 10.1210/jc.2018-01250. [Epub ahead of print]

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

Author information

1
Institute of Experimental Pediatric Endocrinology, Berlin, Germany.
2
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany.
3
Institut für Medizinische Physik und Biophysik, Group Protein X-ray Crystallography and Signal Transduction; Berlin, Germany.
4
Department for Pediatric Endocrinology and Diabetology; Berlin, Germany.
5
Center for Chronically Sick Children, Berlin, Germany.
6
UCL Centre for Nephrology, London, UK.
7
Great Ormond Street Hospital for Children, Renal Unit, London, UK.
8
Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.
9
Department of Clinical Genetics, University Hospital of Wales, Cardiff, UK.
10
Department of Pediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK.
11
Endocrine Unit Massachusetts General Hospital and Harvard Medical School, Boston, Ma, USA.
12
Division of Population Medicine, School of Medicine, Cardiff University, UK.
13
Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, UCL GOS Institute of Child Health, London, UK.
14
University Hospital Heidelberg, Heidelberg, Germany.

Abstract

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.

PMID:
30312418
DOI:
10.1210/jc.2018-01250

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