Journal Article

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. Challis, Lynn E. Pritchard, John W.M. Creemers, Jerome Delplanque, Julia M. Keogh, Jian'an Luan, Nicholas J. Wareham, Giles S.H. Yeo, Sumit Bhattacharyya, Phillipe Froguel, Anne White, I. Sadaf Farooqi and Stephen O'Rahilly

inย Human Molecular Genetics

Volume 11, issue 17, pages 1997-2004
Published in print August 2002 | ISSN: 0964-6906
Published online August 2002 | e-ISSN: 1460-2083 | DOI:ย http://dx.doi.org/10.1093/hmg/11.17.1997
A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism

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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 ๐›ƒ melanocyte-stimulating hormone (๐›ƒ-MSH) and ๐›ƒ-endorphin. ๐›ƒ-TC3 cells transfected with the mutant POMC cDNA produced a mutant ๐›ƒ-MSH/๐›ƒ-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 caseโ€“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.

Journal Article.ย  5191 words.ย  Illustrated.

Subjects: Genetics and Genomics

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