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Human Molecular Genetics, 2002, Vol. 11, No. 17 1997-2004
© 2002 Oxford University Press

A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism

Benjamin G. Challis1,{dagger}, Lynn E. Pritchard2,{dagger}, John W.M. Creemers3,{dagger}, Jerome Delplanque4, Julia M. Keogh1, Jian'an Luan5, Nicholas J. Wareham5, Giles S.H. Yeo1, Sumit Bhattacharyya1, Phillipe Froguel4,6, Anne White2, I. Sadaf Farooqi1 and Stephen O'Rahilly1,*

1University Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK, 2School of Biological Sciences and Faculty of Medicine, Stopford Building, University of Manchester, Manchester M13 9PT, UK and AstraZeneca, Mereside, Alderley Park, Cheshire SK10 4TG, UK, 3Laboratory for Molecular Oncology, Department for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, Herestraat 49, B-3000 Leuven, Belgium, 4Institute of Biology–CNRS 8090, Pasteur Institute of Lille, CHRU of Lille, France, 5Institute of Public Health, Cambridge, UK and 6Barts and The London Genome Centre, Queen Mary's, University of London, UK

Received April 10, 2002; Accepted June 12, 2002

The functional loss of both alleles of the human pro-opiomelanocortin (POMC) gene leads to a very rare syndrome of hypoadrenalism, red hair and early-onset obesity. In order to examine whether more subtle genetic variants in POMC might contribute to early-onset obesity, the coding region of the gene was sequenced in 262 Caucasian subjects with a history of severe obesity from childhood. Two children were found to be heterozygous for a missense mutation, R236G, which disrupts the dibasic cleavage site between ß melanocyte-stimulating hormone (ß-MSH) and ß-endorphin. ß-TC3 cells transfected with the mutant POMC cDNA produced a mutant ß-MSH/ß-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (hMC4R) with an affinity similar to its natural ligands, but had a markedly reduced ability to activate the receptor. This variant co-segregated with early-onset obesity over three generations in one family and was absent in 412 normal weight UK Caucasian controls. Combining the results in UK Caucasians with a new case–control study in French subjects and three previously published reports, mutations disrupting this processing site were present in 0.88% of subjects with early-onset obesity and 0.22% of normal-weight controls. These results suggest that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signalling.

* To whom correspondence should be addressed at: University Departments of Medicine and Clinical Biochemistry, Box 157, Addenbrooke's Hospital, Cambridge CB2 2QR, UK. Tel: +44 1223336855; Fax: +44 1223330598; Email: sorahill{at}hgmp.mrc.ac.uk

{dagger} The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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