Unexpectedly high prevalence of GNAS mutations in children with obesity
Mutations in GNAS, which encodes Gαs (stimulatory G-protein alpha subunit) are known to cause a condition called pseudohypoparathyroidism (PHP). Children with this condition are overweight, have learning difficulties, are often short and have skeletal changes and hormone resistance (read the NEJM editorial here). However, the mechanisms by which one GNAS mutation can lead to a constellation of clinical problems in children are not clear.
Using exome sequencing, we looked at thousands of genes in children from the GOOS cohort. We found 1 in 100 children carried mutations in GNAS. Surprisingly, none of the children identified were previously suspected of having PHP on clinical grounds. Using newly developed assays, which test how Gαs connects to receptors, we found that all the GNAS mutations did affect function which showed that GNAS mutations can present with obesity alone.
Gαs protein is the functional hub for many receptors which respond to different ligands and hormones. In this study, we showed that the majority of mutations in GNAS disrupted signalling by the melanocortin 4 receptor (MC4R), which plays a key role in the regulation of appetite and weight, shedding light on why these children presented with hyperphagia (extreme hunger) and severe obesity. On the flip side, just a fraction of GNAS mutations affected growth hormone–releasing hormone (GHRH) receptor, leading to reduced growth. Only one of 10 children who attained final height had short stature. This explains why doctors did not think the children had PHP and most were tall not short.
We recommend that children with severe obesity should be screened for GNAS deficiency because pathogenic mutations may manifest with obesity alone, and early diagnosis can allow early interventions, improving clinical outcomes.