Obesity-associated GNAS mutations and the melanocortin pathway.

This is the final version. Available from Massachusetts Medical Society via the DOI in this record. BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).Wellcome TrustWellcome TrustResearch EnglandNational Institute for Health Researc

A rare human variant that disrupts GPR10 signalling causes weight gain in mice

This is the author accepted manuscript.Data availability: Exome sequencing data are accessible from the European Genome Archive under a managed access agreement (EGAS00001000124 and EGAS00001000825). Additional data that support the findings of this study are available upon request from the corresponding authors (ISF and SML).Disruption of brain-expressed G-protein-coupled receptor-10 (GPR10) causes obesity in animals. Here, we identified multiple rare variants in GPR10 in people with severe obesity and in normal weight controls. These variants impaired ligand binding and G-protein-dependent signalling in cells. Transgenic mice harbouring a loss of function GPR10 variant found in an obese individual, gained excessive weight due to decreased energy expenditure rather than increased food intake. This evidence supports a role for GPR10 in human energy homeostasis. Therapeutic targeting of GPR10 may represent an effective weight-loss strategy.Wellcome TrustNational Institute for Health Research (NIHR)Bernard Wolfe Health Neuroscience EndowmentBotnar FondationEvelyn TrustResearch EnglandFrench National Research AgencyNational Center for Precision Diabetic MedicineMedical Research Council (MRC)Biotechnology and Biological Sciences Research Council (BBSRC