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

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• The stimulatory G protein alpha subunit (Gαs), encoded by GNAS, is crucial for linking receptors to adenylyl cyclase.
• Maternal GNAS expression is predominant in certain tissues, making heterozygous loss-of-function mutations cause hormonal resistance.
• Somatic gain-of-function mutations lead to hormone-independent endocrine stimulation.

Observation:

• Two unrelated boys exhibited a unique combination of clinical findings suggesting both Gαs gain and loss of function.
• Patients presented with infantile hyponatremia, severe precocious puberty, and skeletal abnormalities.
• An identical de novo heterozygous variant (p.F376V) was identified on the maternal GNAS allele in both patients.

Findings:

• The GNAS p.F376V mutation resulted in a novel phenotype, distinct from known Gαs-related disorders.
• This mutation suggested gain of function at the vasopressin 2 receptor (V2R) and lutropin/choriogonadotropin receptor (LHCGR).
• Increased serum PTH concentrations indicated impaired proximal tubular PTH1 receptor (PTH1R) function, with in vitro studies confirming enhanced basal and blunted stimulated signaling.

Implications:

• The GNAS p.F376V mutation defines a previously unrecognized multisystem disorder.
• This finding broadens the spectrum of GNAS-related disorders and G-protein signaling abnormalities.
• Understanding this mutation's dual effect on receptor signaling provides insights into complex endocrine regulation.