Loss-of-function mutations in ADCY3 cause monogenic severe obesity
File(s)
Accepted version
Accepted version
Author(s)
Type
Journal Article
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 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.
Date Issued
2018-01-08
Date Acceptance
2017-11-14
Citation
NATURE GENETICS, 2018, 50 (2), pp.175-179
ISSN
1061-4036
Publisher
NATURE PUBLISHING GROUP
Start Page
175
End Page
179
Journal / Book Title
NATURE GENETICS
Volume
50
Issue
2
Copyright Statement
© 2018 Nature America Inc., part of Springer Nature. All rights reserved. The final publication is available at https://dx.doi.org/10.1038/s41588-017-0023-6
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000424519200007&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
BODY-MASS INDEX
GENOME-WIDE ASSOCIATION
SUSCEPTIBILITY LOCI
EARLY-LIFE
LIRAGLUTIDE
CHILDHOOD
CHILDREN
INDIVIDUALS
POPULATIONS
EXENDIN-4
Publication Status
Published
Date Publish Online
2018-01-08