A Novel T55A Variant of Gs α Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis

Abstract EN

G-protein coupled receptors (GPCRs) mediate a wide spectrum of biological activities.

The GNAS complex locus encodes the stimulatory alpha subunit of the guanine nucleotide binding protein ( G s α ) and regulates production of the second messenger cyclic AMP (cAMP).

Loss-of-function GNAS mutations classically lead to Albright’s Hereditary Osteodystrophy (AHO) and pseudohypoparathyroidism, often with significant effects on bone formation and mineral metabolism.

We present the case of a child who exhibits clinical features of osteolysis, multiple childhood fractures, and neonatal SIADH.

Exome sequencing revealed a novel de novo heterozygous missense mutation of GNAS (c.163A

In order to further assess whether this unique mutation resulted in a gain or loss of function of G s α , we introduced the mutation into a rat GNAS plasmid and performed functional studies to assess the level of cAMP activity associated with this mutation.

We identified a 64% decrease in isoproterenol-induced cAMP production in vitro, compared to wild type, consistent with loss of G s α activity.

Despite a significant decrease in isoproterenol-induced cAMP production in vitro, this mutation did not produce a classical AHO phenotype in our patient; however, it may account for her presentation with childhood fractures and osteolysis.