• Edson Mendes de Oliveira, Julia M Keogh, Fleur Talbot, Elana Henning, Rachel Ahmed, Aliki Perdikari, Rebecca Bounds, Natalia Wasiluk, Vikram Ayinampudi, Inês Barroso, Jacek Mokrosiński, Deepthi Jyothish, Sharon Lim, Sanjay Gupta, Melanie Kershaw, Cristina Matei, Praveen Partha, Tabitha Randell, Antoinette McAulay, Louise C Wilson, Tim Cheetham, Elizabeth C Crowne, Peter Clayton, and I Sadaf Farooqi.
• From the University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge (E.M.O., J.M.K., F.T., E.H., R.A., A.P., R.B., N.W., V.A., J.M., I.S.F.), the Exeter Centre of Excellence for Diabetes Research, University of Exeter Medical School, Exeter (I.B.), Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham (D.J., M.K.), Broomfield Hospital, Chelmsford (S.L.), Hull University Teaching Hospitals NHS Trust, Hull (S.G.), East and North Hertfordshire NHS Trust Lister Hospital, Stevenage (C.M.), County Durham and Darlington NHS Foundation Trust, Darlington (P.P.), Nottingham Children's Hospital, Nottingham (T.R.), University Hospitals Dorset NHS Foundation Trust, Poole (A.M.), Great Ormond Street Hospital for Children NHS Foundation Trust, London (L.C.W.), the Translational and Clinical Research Institute, Newcastle University, and Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne (T.C.), University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (E.C.C.), and the Division of Developmental Biology and Medicine, University of Manchester, Manchester (P.C.) - all in the United Kingdom.
• N. Engl. J. Med. 2021 Oct 21; 385 (17): 1581-1592.

BackgroundGNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS 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).MethodsWe performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS 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.ResultsAlmost all GNAS 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. GNAS 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 GNAS mutations (3.9±2.6 mIU per liter; P = 0.004).ConclusionsBecause 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. GNAS 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.).Copyright © 2021 Massachusetts Medical Society.

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