Heterozygosity for a POMC-null mutation and increased obesity risk in humans

I. Sadaf Farooqi, Stenvert Drop, Agnes Clements, Julia M. Keogh, Joanna M Biernacka, Sarah Lowenbein, Benjamin G. Challis, Stephen O'Rahilly

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Congenital deficiency of proopiomelanocortin (POMC) results in a syndrome of hypoadrenalism, severe obesity, and altered skin and hair pigmentation. The concept that subtle variation in POMC expression and/or function might contribute to common obesity is suggested by studies reporting linkage of obesity-related traits to a locus on chromosome 2p22 encompassing the POMC gene. We identified a novel homozygous frameshift (C6906del) mutation in POMC in a child of Turkish origin with severe obesity and hypoadrenalism. This mutation would be predicted to lead to the loss of all POMC-derived peptides. The availability of a large extended pedigree provided the opportunity to address whether loss of one copy of the POMC gene was sufficient to alter obesity risk. Twelve relatives were heterozygous for the mutation and 7 were wild type. Of the heterozygotes, 11 of 12 heterozygotes were obese or overweight compared with only 1 of 7 of the wild-type relatives. The mean BMI SD score was 1.7 ± 0.5 in heterozygotes and 0.4 ± 0.4 in the wild-type relatives. Parametric linkage analysis of the trait "overweight" provided statistically significant evidence of linkage with this locus, with a maximum "location score" (comparable with multipoint logarithm of odds scores) of 3.191. We conclude that loss of one copy of the POMC gene predisposes to obesity in humans. Thus, genetic variants having relatively subtle effects on POMC expression and function could influence susceptibility to obesity.

Original languageEnglish (US)
Pages (from-to)2549-2553
Number of pages5
JournalDiabetes
Volume55
Issue number9
DOIs
StatePublished - Sep 2006
Externally publishedYes

Fingerprint

Pro-Opiomelanocortin
Obesity
Mutation
Heterozygote
Adrenal Insufficiency
Morbid Obesity
Genes
Skin Pigmentation
Frameshift Mutation
Pedigree
Hair
Chromosomes
Peptides

Keywords

  • POMC, proopiomelanocortin

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Farooqi, I. S., Drop, S., Clements, A., Keogh, J. M., Biernacka, J. M., Lowenbein, S., ... O'Rahilly, S. (2006). Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes, 55(9), 2549-2553. https://doi.org/10.2337/db06-0214

Heterozygosity for a POMC-null mutation and increased obesity risk in humans. / Farooqi, I. Sadaf; Drop, Stenvert; Clements, Agnes; Keogh, Julia M.; Biernacka, Joanna M; Lowenbein, Sarah; Challis, Benjamin G.; O'Rahilly, Stephen.

In: Diabetes, Vol. 55, No. 9, 09.2006, p. 2549-2553.

Research output: Contribution to journalArticle

Farooqi, IS, Drop, S, Clements, A, Keogh, JM, Biernacka, JM, Lowenbein, S, Challis, BG & O'Rahilly, S 2006, 'Heterozygosity for a POMC-null mutation and increased obesity risk in humans', Diabetes, vol. 55, no. 9, pp. 2549-2553. https://doi.org/10.2337/db06-0214
Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka JM, Lowenbein S et al. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes. 2006 Sep;55(9):2549-2553. https://doi.org/10.2337/db06-0214
Farooqi, I. Sadaf ; Drop, Stenvert ; Clements, Agnes ; Keogh, Julia M. ; Biernacka, Joanna M ; Lowenbein, Sarah ; Challis, Benjamin G. ; O'Rahilly, Stephen. / Heterozygosity for a POMC-null mutation and increased obesity risk in humans. In: Diabetes. 2006 ; Vol. 55, No. 9. pp. 2549-2553.
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