Centre National de la Recherche Scientifique (CNRS) UMR 8199, Institut Pasteur de Lille, University of Lille, Lille, France.
Department of Genomics of Common Disease, Imperial College London, London, UK.
Nat Genet. 2018 Feb;50(2):175-179. doi: 10.1038/s41588-017-0023-6. Epub 2018 Jan 8.
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 . 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 . We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity. 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.
对单基因肥胖形式的研究表明，中枢瘦素-黑皮质素途径在控制能量平衡、食欲和体重方面起着关键作用。大多数功能丧失突变（主要是隐性或共显性）已在直接参与瘦素-黑皮质素信号转导的基因中被鉴定出来。然而，这些基因仅能解释<5%的肥胖病例，主要来自于杂合人群。我们之前曾表明，在巴基斯坦的一个近亲人群中，已知肥胖相关基因的隐性突变解释了~30%的严重肥胖病例。这些数据表明，在该人群中也可以发现新的单基因肥胖形式。在这里，我们鉴定并对来自近亲巴基斯坦家庭的严重肥胖儿童以及一名欧裔美国裔严重肥胖儿童的复合杂合突变的编码腺苷酸环化酶 3 的 ADCY3 基因中的纯合突变进行了功能分析。这些发现强调了 ADCY3 作为能量平衡的重要介质，以及在肥胖治疗中作为有吸引力的药理学靶点。
