In a new study published in The New England Journal of Medicine, a team led by Professor Sadaf Farooqi, found that 1 in 100 children with severe obesity from the GOOS cohort, have mutations in GNAS which encodes Gαs (stimulatory G-protein alpha subunit). GNAS mutations typically cause a condition called pseudohypoparathyroidism (PHP) and impair signalling by Gαs-coupled GPCRs, leading to short stature, obesity, learning difficulties and hormone resistance when inherited on the maternal allele (imprinting). Here, the team showed GNAS mutations impair MC4R signalling, which explains hyperphagia and obesity in children and paves the way for new treatments.
Edson Mendes de Oliveira, first author of the study says:
We developed a protein-protein interaction assay to study signalling by multiple GPCRs that could mediate the clinical condition. Most mutations impaired coupling of Gαs to the receptor and would not have been detected in the current GNAS bioactivity assay
On the flip side, very few GNAS mutations affected growth hormone–releasing hormone (GHRH) receptor signalling, which explains why most children did not have reduced growth, previously thought to be a typical clinical feature. Overall, the variable clinical spectrum in children with GNAS deficiency could be explained by the results of the molecular assays.
This work demonstrates that disruption of the melanocortin pathway can cause childhood onset obesity through a range of mechanisms. We recommend that children with severe obesity should undergo screening for GNAS deficiency because pathogenic mutations may manifest with obesity alone, and early diagnosis allows for treatments which improve clinical outcomes
says Professor Farooqi.
The New England Journal of Medicine selected this study for a Quick Take video. The illustrative summary of the research findings is available on the NEJM website.