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 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.Obesity, with its complications, has emerged as a major contributor to the global health burden and has assumed the status of a pandemic 6 .At least 2.8 million people die each year as a consequence of being overweight or obese 7 .Although obesity is one of the most heritable diseases 8 , the genetic etiology of a large proportion of obesity cases remains elusive.Here we performed whole-exome sequencing (WES) analysis in 138 probands who presented with severe, early-onset obesity (body mass index (BMI) s.d.score (SDS) ≥3) and their available family members (n = 117) from consanguineous families from the Punjab province of Pakistan.These 138 probands were part of a larger cohort of 195 probands, 57 of whom were previously