ESPEYB19 15. Editors’ Choice Obesity (3 abstracts)
15.3. Obesity-associated GNAS mutations and the melanocortin pathway
Mendes de Oliveira E , Keogh JM , Talbot F , Henning E , Ahmed R , Perdikari A , Bounds R , Wasiluk N , Ayinampudi V , Barroso I , Mokrosinski J , Jyothish D , Lim S , Gupta S , Kershaw M , Matei C , Partha P , Randell T , McAulay A , Wilson LC , Cheetham T , Crowne EC , Clayton P & Farooqi IS
N Engl J Med. 2021;385(17):1581-92. doi: 10.1056/NEJMoa2103329.PubMed ID: 34614324
Brief Summary: The authors performed whole exome sequencing in 2548 children with severe obesity and identified 22 GNAS mutation carriers, almost all of which disrupted melanocortin 4 receptor (MC4R) signaling.
The gene GNAS encodes the stimulatory G-protein alpha subunit protein, which is a key component of many hormone receptors (GPCRs). Deleterious GNAS mutations are well known to cause Albright’s hereditary osteodystrophy, characterised by short stature and skeletal abnormalities. Furthermore, as it is a paternally imprinted (silenced) gene, maternally-inherited GNAS mutations also cause resistance to parathyroid hormone (pseudohypoparathyroidism) as well as resistance to diverse other hormones.
A characteristic effect of pseudohypoparathyroidism on early onset obesity associated with hyperphagia has long been recognised (1), however the underlying mechanism was unknown. Here, the authors show that 22 (of 2548) children with severe obesity carried deleterious mutations in GNAS, most of which disrupted signaling of MC4R, the well-described hypothalamic regulator of appetite and weight gain. This confirms GNAS as a cause for monogenic obesity associated with hyperphagia. The authors comment that severely obese patients with GNAS mutations should respond to the MC4R agonist, setmelanotide.
In addition, the wide involvement of the stimulatory G-protein alpha subunit across diverse hormone receptors means that affected children have a complex endocrine phenotype. 6 of the 11 patients who were age 12 to 18 years had evidence of reduced growth (mean standard-deviation score for height, −0.90), and in vitrotheir mutations disrupted growth hormone-releasing hormone receptor signaling. Furthermore, GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and high TSH levels (mean [±S.D.], 8.4±4.7 mIU/l).
By contrast, although most identified GNAS mutations impaired PTH receptor signaling, only one patient had subcutaneous ossifications, and 10 patients showed mild brachydactyly, two characteristics of Albright’s hereditary osteodystrophy (OMIM 103580).
Reference: 1. Ong KK, Amin R, Dunger DB. Pseudohypoparathyroidism–another monogenic obesity syndrome. Clin Endocrinol (Oxf). 2000 Mar;52(3):389–91. PMID: 10718839.
Volume 19
Article tools
My recent searches
My recently viewed abstracts
Authors
ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more