Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin-melanocortin pathway in controlling energy balance, appetite and body weight ¹ . The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin-melanocortin signaling. These genes, however, only explain obesity in <5% of cases, predominantly from outbred populations ² . We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity^3-5. These data suggested that new monogenic forms of obesity could also be identified in this population. Here we identify and functionally characterize homozygous mutations in the ADCY3 gene encoding adenylate cyclase 3 in children with severe obesity from consanguineous Pakistani families, as well as compound heterozygous mutations in a severely obese child of European-American descent. These findings highlight ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity.

中文翻译：

---

ADCY3中的功能丧失突变导致单基因严重肥胖。

对肥胖的单基因形式的研究表明，中央瘦素​​-黑皮质素途径在控制能量平衡，食欲和体重中起着关键性作用¹。大多数功能丧失突变（大多数为隐性或共显性）已在直接参与瘦素-黑皮质素信号转导的基因中得到鉴定。然而，这些基因仅在＜5％的病例中解释了肥胖症，主要来自远亲群体²。我们之前的研究表明，在巴基斯坦的近亲人群中，已知肥胖相关基因的隐性突变可解释约30％的严重肥胖病例^3-5。这些数据表明，也可以在该人群中发现肥胖的新的单基因形式。在这里，我们确定并功能性地表征了来自血缘巴基斯坦家庭的严重肥胖儿童的ADCY3基因编码腺苷酸环化酶3的纯合突变，以及在具有欧洲裔血统的严重肥胖儿童中的复合杂合突变。这些发现突显了ADCY3是能量稳态的重要介质，并且在肥胖症治疗中是有吸引力的药理学靶标。