The role of genetic and epigenetic GNAS alterations in the development of early-onset obesity

Background: GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes Gs alpha, the alpha subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in GNAS are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that Gs alpha serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, beta 2- and beta 3-adrenoceptors, and corticotropinreleasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic GNAS changes. Scope of review: This review examines the structure and function of GNAS and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying Gs alpha deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition. Major conclusions: Gs alpha deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for GNAS defects is recommended, to enhance the molecular diagnosis and management of this condition.