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Obesity-Associated GNAS Mutations and the Melanocortin Pathway
The New England Journal of Medicine ( IF 158.5 ) Pub Date : 2021-10-06 , DOI: 10.1056/nejmoa2103329
Edson Mendes de Oliveira 1 , Julia M Keogh 1 , Fleur Talbot 1 , Elana Henning 1 , Rachel Ahmed 1 , Aliki Perdikari 1 , Rebecca Bounds 1 , Natalia Wasiluk 1 , Vikram Ayinampudi 1 , Inês Barroso 1 , Jacek Mokrosiński 1 , Deepthi Jyothish 1 , Sharon Lim 1 , Sanjay Gupta 1 , Melanie Kershaw 1 , Cristina Matei 1 , Praveen Partha 1 , Tabitha Randell 1 , Antoinette McAulay 1 , Louise C Wilson 1 , Tim Cheetham 1 , Elizabeth C Crowne 1 , Peter Clayton 1 , I Sadaf Farooqi 1
Affiliation  

Background

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).

Methods

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.

Results

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).

Conclusions

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. (Funded by Wellcome and others.)



中文翻译:

肥胖相关的 GNAS 突变和黑皮质素途径

背景

GNAS编码 Gα s(刺激性 G 蛋白 α 亚基)蛋白,该蛋白介导 G 蛋白偶联受体 (GPCR) 信号传导。GNAS突变导致称为奥尔布赖特遗传性骨营养不良综合征的发育迟缓、身材矮小和骨骼异常。由于印记,母体等位基因的突变也会导致肥胖和激素抵抗(假性甲状旁腺功能减退)。

方法

我们对 2548 名患有严重肥胖症的儿童进行了外显子组测序和靶向重测序,我们意外地发现了 22名 GNAS突变携带者。我们研究了GNAS突变对黑皮质素 4 受体 (MC4R) 信号传导的影响是否解释了肥胖,以及患者的可变临床谱是否可以通过分子测定的结果来解释。

结果

几乎所有GNAS突变都会损害 MC4R 信号传导。在 11 名 12 至 18 岁的患者中,共有 6 名生长缓慢。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,但不影响该信号通路的突变携带者的生长不受影响(身高的平均标准差评分分别为 -0.90 和 0.75;P=0.02) . 在研究之前或期间达到最终身高的 10 名患者中,只有 1 名身材矮小。与未患有GNAS的 340 名严重肥胖儿童相比,促甲状腺激素受体信号传导受损的GNAS突变与发育迟缓和促甲状腺激素水平(平均 [±SD],8.4±4.7 mIU/L)相关。突变(每升 3.9±2.6 mIU;P=0.004)。

结论

由于致病突变可能仅在肥胖中表现出来,因此筛查重度肥胖儿童是否存在 GNAS缺陷可能有助于早期诊断、改善临床结果,而黑皮质素激动剂可能有助于减轻体重。通过无偏基因检测鉴定的GNAS突变对导致临床异质性的 GPCR 信号通路有不同的影响。单基因疾病在临床上比其经典描述所暗示的变化更大。(由 Wellcome 和其他人资助。)

更新日期:2021-10-07
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