GNAS Mutations Affect MC4R Signaling in Some Severe Childhood-Onset Obesity

childhood obesity
Childhood obesity problem and weight loss. Fat boy at a nutritionist appointment. Overweight boy consulting with doctor in office. Doctor examining fat boy in clinic. Doctor measuring overweight boy.
Investigators examined whether GNAS mutations on melanocortin 4 receptor signaling contributed to severe childhood obesity.

GNAS mutations can cause obesity in children due to their affect on melanocortin 4 receptor (MC4R) signaling, according to a study in the New England Journal of Medicine.

Investigators conducted exome sequencing and targeted resequencing in 2548 children with severe obesity and unexpectedly found GNAS mutations in 22 of the study participants. The researchers then sought to determine the effect of GNAS mutations on signaling by the stimulatory G-protein alpha subunit (Gαs)-coupled MC4R, which they noted “is critical to the regulation of appetite and weight and in which heterozygous loss-of-function mutations are the most common monogenic form of obesity.”

The mean (±SD) gestational age at birth of the children who were GNAS mutation carriers was 39.6±1.7 weeks, and their mean SD score for birth weight was −0.72, which was consistent with mild intrauterine growth restriction. In the first 6 months of life, all patients had accelerated weight gain that led to severe obesity in childhood.

The study authors identified 19 heterozygous GNAS mutations in 22 children with severe childhood-onset obesity, including 16 missense, 2 nonsense, and 1 frameshift mutation. Of the 16 missense mutations, 14 impaired the interaction between Gαs and MC4R, MC4R-mediated cyclic AMP accumulation, MC4R-independent cyclic AMP accumulation, or all of these.

Children who had GNAS mutations had accelerated growth before age 12 years, with a mean SD score for height of 0.92. In 14 of 18 children with GNAS mutations, growth trajectories before age 12 years were comparable with those in other severely obese children. Six of 11 GNAS mutation carriers had a reduction in pubertal growth spurt, final height, or both.

Participants who had a reduction in pubertal growth spurt carried GNAS mutations that impaired growth hormone–releasing hormone receptor signaling (mean SD score for height, −0.90). Growth was consistent with predicted percentiles in children with GNAS mutations that did not impair function (mean SD score for height, 0.75; P = .02).

Participants who were carriers of loss-of-function GNAS mutations had significantly higher mean (±SD) thyrotropin levels compared with 340 severely obese children from the Genetics of Obesity Study cohort (8.4±4.7 vs 3.9±2.6 mIU/L, respectively; P = .004). Carriers of mutations with wild-type–like activity had comparable thyrotropin levels.

Researchers noted caution is need when interpreting specific assay values because of the limited effects of multiple testing.

“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,” the investigators concluded.

Disclosure: Some of the study authors declared affiliations with pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.


Mendes de Oliveira E, Keogh JM, Talbot F, et al. Obesity-associated GNAS mutations and the melanocortin pathway. N Engl J Med. 2021;385(17):1581-1592. doi:10.1056/NEJMoa2103329