Loss-of-function mutations in ADCY3 cause monogenic severe obesity

Abstract

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.

Genome wide association study in 3,173 outbred rats identifies multiple loci for body weight, adiposity, and fasting glucose

“…In addition, using gene expression data from HS liver, we identified Krtcap3 and Slc30a3 as likely mediators of fat pad weight at this locus. Although Adcy3 has been found to play a role in both complex and monogenic forms of obesity (Nordman et al 2008;Speliotes et al 2010;Grarup et al 2018;Saeed et al 2018) and…”

Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity

“…We performed a literature search to identify genes related to the melanocortin pathway and the development of the hypothalamus (1,5,12,18,19,21,(26)(27)(28)(29)(30)(31)(32)(33). The 24 genes included in the panel were: (1) genes in which variants have previously been reported to cause or associate with obesity (ADCY3, BDNF, CPE, GRPR, LEP, LEPR, LRP2, MC3R, MC4R, MRAP2, MYT1L, NPY, NTRK2, PCSK1, POMC, SH2B1, SIM1, TUB) and (2) genes previously reported in animal models/linkage analysis/CNV studies to be involved in the melanocortin pathway or development of hypothalamus (ARNT2, ISL1, NEUROG3, OTP, OXT, POU3F2).…”

Primary Cilia as Signaling Hubs in Health and Disease

“…[10,132] Genes associated with BBS and ALMS encode ciliary proteins, and the mutated proteins impair the function of primary cilia in hypothalamic neurons, which is the potential cause of obesity in these disorders. [142][143][144][145] ADCY3 is bound to Gs in primary cilia. Melanocortin 4 receptor (MC4R), a common receptor for αMSH and AgRP, is strongly expressed in the ciliated PVN neurons expressing single-minded 1 (SIM1), where αMSH and AgRP activate and inhibit MC4R, respectively.…”