Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin–melanocortin pathway in controlling energy balance, appetite and body weight1. 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 populations2. We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity3,4,5. 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.

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The authors thank the patients and their families for participation in the study. We are grateful to A. W. Rathore for clinical facilitation, Z. Gilani for his advice regarding ADCY3 molecular modeling, M. Boissel for help with statistical analyses, and Q. Ain and I. Qureshi for their technical assistance. This study was supported by the Fédération de Recherche 3508 Labex EGID (European Genomics Institute for Diabetes; ANR-10-LABX-46) (to P.F.), the ANR Equipex 2010 session (ANR-10-EQPX-07-01; ‘LIGAN-PM’) (to P.F.), the European Community (FEDER) and the Region Hauts-de-France (to P.F.). The research leading to this study was also supported by funding from the European Research Council GEPIDIAB 294785 (P.F.) and the Pakistan Academy of Sciences (to M. Arslan).

Author information


  1. Centre National de la Recherche Scientifique (CNRS) UMR 8199, Institut Pasteur de Lille, University of Lille, Lille, France

    • Sadia Saeed
    • , Amélie Bonnefond
    • , Emmanuelle Durand
    • , Emmanuel Vaillant
    • , Franck De Graeve
    • , Iandry Rabearivelo
    • , Olivier Sand
    • , Gurvan Queniat
    • , Raphaël Boutry
    • , Amar Abderrahmani
    •  & Philippe Froguel
  2. Department of Genomics of Common Disease, Imperial College London, London, UK

    • Sadia Saeed
    • , Filippo Tamanini
    • , Amar Abderrahmani
    •  & Philippe Froguel
  3. Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

    • Muhammad Usman Mirza
  4. Department of Pediatric Endocrinology, Children’s Hospital, Lahore, Pakistan

    • Jaida Manzoor
  5. Centre for Research in Molecular Medicine, University of Lahore, Lahore, Pakistan

    • Qasim M. Janjua
    •  & Muhammad Arslan
  6. Department of Biological Sciences, Forman Christian College, Lahore, Pakistan

    • Sadia M. Din
    • , Attiya Haseeb
    •  & Muhammad Arslan
  7. CNRS, Laboratory of Membrane Chemistry and Biology (CBMN), UMR 5248, Bordeaux, France

    • Julien Gaitan
    • , Alexandra Milochau
    •  & Jochen Lang
  8. Department of Sciences and Technology, University of Bordeaux, Talence, France

    • Julien Gaitan
    • , Alexandra Milochau
    •  & Jochen Lang
  9. Department of Pediatrics, Zuyderland Hospital, Heerlen, The Netherlands

    • Dina A. Schott
  10. Department of Pediatrics, Punjab Medical College, Faisalabad, Pakistan

    • Hina Ayesha
  11. Department of Pediatrics, Mayo Hospital, King Edward Medical University, Lahore, Pakistan

    • Muhammad Ali
  12. Children Hospital and Institute of Child Health, Multan, Pakistan

    • Waqas I. Khan
  13. Department of Pediatrics, Fatima Memorial Hospital, Lahore, Pakistan

    • Taeed A. Butt
  14. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands

    • Tuula Rinne
  15. Department of Clinical Genetics and GROW–School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands

    • Connie Stumpel


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S.S., A.B., M. Arslan and P.F. designed the study and wrote the first draft of the paper. S.S., Q.M.J., S.M.D., A.H. and M. Arslan collected samples and performed biochemical analyses. A.B., E.D., O.S., T.R., E.V., I.R., S.S. and F.D.G. performed whole-exome sequencing and analyzed the genetic data. J.M., H.A., D.A.S., M. Ali, W.I.K., T.A.B. and C.S. identified and recruited families with obese individuals. F.T., J.G., A.M., G.Q., R.B., A.A. and J.L. performed the functional experiments and analyzed the data. M.U.M. performed the structural analysis. All authors contributed to the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Philippe Froguel.

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