HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Farooqi, I. S. Articles by O’Rahilly, S. Search for Related Content PubMed PubMed Citation Articles by Farooqi, I. S. Articles by O’Rahilly, S. Social Bookmarking                What's this?

Heterozygosity for a POMC-Null Mutation and Increased Obesity Risk in Humans

¹ University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, U.K
² Sofia Children's Hospital, Erasmus University, Rotterdam, the Netherlands
³ MCH Westeinde, The Hague, the Netherlands
⁴ Medical Genetics Department, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, U.K

Address correspondence and reprint requests to Stephen O’Rahilly, University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, CB2 2XY, U.K. E-mail: so104{at}medschl.cam.ac.uk

Abbreviations: POMC, proopiomelanocortin

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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				V. F. Bumaschny, F. S. J. de Souza, R. A. Lopez Leal, A. M. Santangelo, M. Baetscher, D. H. Levi, M. J. Low, and M. Rubinstein Transcriptional Regulation of Pituitary POMC Is Conserved at the Vertebrate Extremes Despite Great Promoter Sequence Divergence Mol. Endocrinol., November 1, 2007; 21(11): 2738 - 2749. [Abstract] [Full Text] [PDF]

				Y. C. L. Tung, D. Rimmington, S. O'Rahilly, and A. P. Coll Pro-Opiomelanocortin Modulates the Thermogenic and Physical Activity Responses to High-Fat Feeding and Markedly Influences Dietary Fat Preference Endocrinology, November 1, 2007; 148(11): 5331 - 5338. [Abstract] [Full Text] [PDF]

				I. J. Jackson, P. S. Budd, M. Keighren, and L. McKie Humanized MC1R transgenic mice reveal human specific receptor function Hum. Mol. Genet., October 1, 2007; 16(19): 2341 - 2348. [Abstract] [Full Text] [PDF]

				Y. Seng Lee, L. Kok Seng Poh, B. Lay Kee Kek, and K. Yin Loke The Role of Melanocortin 3 Receptor Gene in Childhood Obesity Diabetes, October 1, 2007; 56(10): 2622 - 2630. [Abstract] [Full Text] [PDF]

				M. Lee, A. Kim, S. C. Chua Jr., S. Obici, and S. L. Wardlaw Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E121 - E131. [Abstract] [Full Text] [PDF]

				I. S. Farooqi and S. O'Rahilly Genetics of Obesity in Humans Endocr. Rev., December 1, 2006; 27(7): 710 - 718. [Abstract] [Full Text] [PDF]

				K. E. Foster-Schubert and D. E. Cummings Emerging Therapeutic Strategies for Obesity Endocr. Rev., December 1, 2006; 27(7): 779 - 793. [Abstract] [Full Text] [PDF]