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

Sadia Saeed, Amelie Bonnefond, Filippo Tamanini, Muhammad Usman Mirza, Jaida Manzoor, Qasim M. Janjua, Sadia M. Din, Julien Gaitan, Alexandra Milochau, Emmanuelle Durand, Emmanuel Vaillant, Attiya Haseeb, Franck De Graeve, Iandry Rabearivelo, Olivier Sand, Gurvan Queniat, Raphael Boutry, Dina A. Schott, Hina Ayesha, Muhammad AliWaqas I. Khan, Taeed A. Butt, Tuula Rinne, Connie Stumpel, Amar Abderrahmani, Jochen Lang, Muhammad Arslan, Philippe Froguel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

69 Citations (Web of Science)

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 similar to 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.
Original languageEnglish
Pages (from-to)175-179
Number of pages5
JournalNature Genetics
Volume50
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • BODY-MASS INDEX
  • GENOME-WIDE ASSOCIATION
  • SUSCEPTIBILITY LOCI
  • EARLY-LIFE
  • LIRAGLUTIDE
  • CHILDHOOD
  • CHILDREN
  • INDIVIDUALS
  • POPULATIONS
  • EXENDIN-4

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