Obesity-Associated GNAS Mutations and the Melanocortin Pathway

This study investigated the role of GNAS mutations in severe childhood obesity and their impact on melanocortin 4 receptor (MC4R) signaling. Using exome sequencing and targeted resequencing in 2548 severely obese children, 22 GNAS mutation carriers were identified. Functional assays revealed that these mutations impaired MC4R and other G protein-coupled receptor (GPCR) signaling pathways, contributing to obesity and variable clinical features such as developmental delay, short stature, and hormone resistance. The findings suggest that GNAS screening in severe obesity cases could enable early diagnosis and targeted therapies, including MC4R agonists for weight management.

This study investigated the role of GNAS mutations in severe childhood obesity and their impact on melanocortin 4 receptor (MC4R) signaling. Using exome sequencing and targeted resequencing in 2548 severely obese children, 22 GNAS mutation carriers were identified. Functional assays revealed that these mutations impaired MC4R and other G protein-coupled receptor (GPCR) signaling pathways, contributing to obesity and variable clinical features such as developmental delay, short stature, and hormone resistance. The findings suggest that GNAS screening in severe obesity cases could enable early diagnosis and targeted therapies, including MC4R agonists for weight management.