Background

GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes G_sα, the α subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in GNAS are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that G_sα serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, β₂- and β₃-adrenoceptors, and corticotropin-releasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic GNAS changes.

Scope of review

This review examines the structure and function of GNAS and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying G_sα deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition.

Major conclusions

G_sα deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for GNAS defects is recommended, to enhance the molecular diagnosis and management of this condition.

中文翻译：

---

遗传和表观遗传 GNAS 改变在早发性肥胖发展中的作用

背景

GNAS（鸟嘌呤核苷酸结合蛋白，α刺激）是一种印记基因，编码 G _s α，即异源三聚体刺激性 G 蛋白的 α 亚基。该亚基介导多种 G 蛋白偶联受体 (GPCR) 的信号传导，包括黑皮质素 4 受体 (MC4R)，其在调节食物摄入、能量稳态和体重方面发挥着关键作用。已知GNAS的遗传或表观遗传改变会导致其不同亚型的假性甲状旁腺功能减退症，并且最近与孤立的早发性严重肥胖症相关。_{鉴于 G s} α 具有多种生物学功能，涉及多种 GPCR（例如 MC4R、β ₂ - 和 β _{3 -}肾上腺素受体以及促肾上腺皮质激素释放激素受体）的多种分子机制与严重早发性早发性早发性重症的病理生理学有关。遗传或表观遗传GNAS变化导致的肥胖。

审查范围

这篇综述检查了GNAS的结构和功能，并概述了由该基因缺陷引起的疾病，这些疾病可能以早发性肥胖为特征。_{此外，它阐明了 G s} α 缺乏引起的早发性肥胖的潜在分子机制，强调了它们对这种复杂疾病的诊断、管理和治疗的一些影响。

主要结论

G _s α 缺乏症是导致早发性严重肥胖症的一个未被充分认识的原因。因此，建议对不明原因的严重肥胖儿童进行GNAS缺陷筛查，以加强对该疾病的分子诊断和管理。