Obesity-Associated <i>GNAS</i> Mutations and the Melanocortin Pathway.

Abstract

<i>GNAS</i> encodes the Gα_s (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. <i>GNAS</i> 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). We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 <i>GNAS</i> mutation carriers. We investigated whether the effect of <i>GNAS</i> 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. Almost all <i>GNAS</i> 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. <i>GNAS</i> 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 <i>GNAS</i> mutations (3.9±2.6 mIU per liter; P = 0.004). Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for <i>GNAS</i> deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. <i>GNAS</i> 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.).