英国威康医学研究委员会 I. Sadaf Farooqi团队研究了GNAS突变和黑皮质素途径与肥胖的相关性。相关论文于2021年10月6日发表于《新英格兰医学杂志》上。
几乎所有GNAS突变都损害了MC4R信号。11名年龄在12至18岁的患者中，共有6名生长发育不良。在这些患者中，突变破坏了生长激素释放激素受体信号传导，但在不影响该信号传导途径的突变携带者中，生长发育不受影响。在研究之前或研究期间达到最终身高的10名患者中，只有1名身材矮小。与340名未发生GNAS突变的严重肥胖儿童（3.9±2.6 mIU/L）相比，损害促甲状腺激素受体信号的GNAS突变与发育迟缓相关，且促甲状腺激素水平较高（8.4±4.7 mIU/L）。
Title: Obesity-Associated GNAS Mutations and the Melanocortin Pathway
Author: Edson Mendes de Oliveira, Ph.D.,, Julia M. Keogh, B.Sc.,, Fleur Talbot, M.B., B.S., Ph.D.,, Elana Henning, B.Soc.Sc.,, Rachel Ahmed, B.Sc.,, Aliki Perdikari, Ph.D.,, Rebecca Bounds, Ph.D.,, Natalia Wasiluk, M.Sc.,, Vikram Ayinampudi, B.Sc.,, Inês Barroso, Ph.D.,, Jacek Mokrosiński, Ph.D.,, Deepthi Jyothish, M.B., B.S.,, Sharon Lim, M.B., Ch.B.,, Sanjay Gupta, M.B., B.S.,, Melanie Kershaw, M.B., Ch.B.,, Cristina Matei, M.D.,, Praveen Partha, M.B., B.S.,, Tabitha Randell, M.B., Ch.B.,, Antoinette McAulay, M.B., Ch.B., M.D.,, Louise C. Wilson, M.B., Ch.B.,, Tim Cheetham, M.B., Ch.B., M.D.,, Elizabeth C. Crowne, M.B., B.S., M.D.,, Peter Clayton, M.B., Ch.B., M.D.,, and I. Sadaf Farooqi, M.B., Ch.B., Ph.D.
GNAS 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).
We 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.
Almost 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).
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. 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.