Germline-derived GNAS-Gsα variants associated with both gain-of-function and loss-of-function phenotypes

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Germline GNAS inactivating mutations cause hormonal resistance.
• Activating GNAS mutations typically lead to constitutive cyclic adenosine monophosphate (cAMP) stimulation.
• Germline activating GNAS variants have been linked to nephrogenic syndrome of inappropriate antidiuresis (NSIAD).

Purpose of the Study:

• To characterize GNAS variants in families presenting with symptoms of both Gsα loss-of-function and NSIAD.
• To investigate the clinical, genetic, structural, and functional properties of identified GNAS variants.

Main Methods:

• Performed GNAS gene sequencing in affected families.
• Conducted in vitro functional studies using dual luciferase assays.
• Performed protein structural analyses of identified GNAS variants.

Main Results:

• Identified two heterozygous GNAS variants (c.592C>T p.(Leu198Phe) and c.501C>G p.(Asn167Lys)) in four families, maternally inherited.
• Observed NSIAD in one mother with a maternally inherited variant.
• Functional studies showed altered activity in the arginine vasopressin receptor 2 (AVPR2)-AVP system and reduced parathyroid hormone (PTH)-stimulated activity for variant Gsα proteins compared to wild-type.

Conclusions:

• This study supports the existence of germline GNAS variants that manifest with both gain-of-function and loss-of-function characteristics.
• The identified variants may have distinct impacts on interactions with AVPR2 and PTH 1 receptors.