Obesity-Associated <i>GNAS</i> Mutations and the Melanocortin Pathway
Edson Mendes de Oliveira, Julia M. Keogh, Fleur Talbot, Elana Henning, Rachel R. Ahmed, Aliki Perdikari, Rebecca Bounds, Natalia Wasiluk, V. Ayinampudi, Inês Barroso, Jacek Mokrosiński, Deepthi Jyothish, Sharon Lim, Sanjay Gupta, Melanie Kershaw, Cristina Matei, Praveen Partha, T. Randell, Antoinette McAulay, Louise C. Wilson, Tim Cheetham, Elizabeth Crowne, Peter Clayton, I. Sadaf Farooqi
Abstract
BACKGROUND: 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: 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: mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: 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.).