Rare GNAS mutations may underpin severe obesity even in absence of pseudohypoparathyroidism

medwireNews: Researchers have identified pathogenic mutations in the gene encoding the stimulatory G-protein alpha subunit (Gαs) protein in children with severe obesity but few or no clinical signs of pseudohypoparathyroidism.

Mutations in GNAS are responsible for Albright’s hereditary osteodystrophy (otherwise known as pseudohypoaldosteronism). As such, they are routinely tested for only in children with “the classic features of pseudohypoparathyroidism”, say I Sadaf Farooqi (Addenbrooke’s Hospital, Cambridge, UK)

The 2548 study participants – a subset of the 7000 enrolled in the Genetics of Obesity Study – all developed severe obesity (BMI standard deviation score >3.0) within the first 10 years of life but known monogenic causes of obesity had been ruled out.

However, exome sequencing revealed 19 heterozygous GNAS mutations in 22 of these patients, comprising 16 missense, two nonsense and one frameshift mutation.

These 22 patients developed obesity by the age of 3 years, the majority within their first year, and most of those tested early in life had mild or no elevation of thyroid-stimulating hormone (TSH) levels. Stronger laboratory evidence of pseudohypoparathyroidism emerged only later in life, and not in all patients.

The researchers found that although the 16 patients with missense mutations had relatively normal levels of Gαs, either the ability of these proteins to bind to G protein–coupled receptors (GPCRs) was impaired or the production of cyclic AMP reduced, or both occurred. The protein was absent in patients with nonsense and frameshift mutations.

Farooqi and team looked specifically at GPCRs involved in hormone resistance and weight regulation. Of particular note, they found that 14 of the 16 missense mutations impaired signalling through the melanocortin 4 receptor (MC4R), which is the most common known cause of monogenic obesity.

These findings are “sufficient to explain early-onset obesity” in these 14 patients, write the researchers in The New England Journal of Medicine, noting that many of them reportedly had hyperphagia, which is “a cardinal feature of MC4R deficiency”.

Fifteen of the 16 missense mutations impaired signalling through the β2- and β3-adrenoreceptors, which the team says could explain features such as “hypothermia in infancy, bradycardia, constipation, urinary retention, bronchoconstriction, and the reduced lipolytic response to epinephrine.”

Eleven patients had TSH resistance, consistent with an adverse effect of GNAS mutations on signalling through the Gαs-coupled TSH receptor. All 17 patients with developmental delay had impairments in this signalling pathway, and the researchers note that TSH resistance can also result in a reduced metabolic rate.

“Since GNAS mutations impaired signaling by β2- and β3-adrenoreceptors and by thyrotropin receptors, reduced energy expenditure, lipolysis, or both may also contribute to weight gain”, they observe.

Just one of the study participants had short stature at study enrolment, despite the known role of Gαs in growth. However, six of 11 children with available data had a reduced pubertal growth spurt, and these patients were found to have GNAS mutations that altered signalling through the growth hormone–releasing hormone receptor. One of the 10 patients who attained final adult height during follow-up had short stature.

Finally, although 10 patients had brachydactyly, this “was often subtle” and just one had subcutaneous ossifications, despite the presence of GNAS mutations causing parathyroid hormone resistance, which could potentially lead to hypocalcaemia.

The researchers stress the “considerable clinical variability” generated by the missense GNAS mutations.

They therefore “conclude that screening for mutations in GNAS should be incorporated into the diagnostic workup for severe childhood-onset obesity.”

The team writes: “Early diagnosis of GNAS deficiency guides monitoring for hormone resistance, recognition of hypocalcemia as a cause of seizures, and treatment with levothyroxine when appropriate.

“Growth velocity and pubertal development should be monitored so that growth hormone therapy can be initiated before fusion of the growth plate.”

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

N Engl J Med 2021; 385: 1581–1592
Martin Savage
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