Original Paper

A Two-Base Deletion -439delGC in the Melanocortin-4 Receptor Promoter Associated with Early-Onset Obesity
Kaisa Valli-Jaakola^a, Jorma J. Palvimo^{b, c}, Marita Lipsanen-Nyman^d, Veikko Salomaa^e, Leena Peltonen^{f, g, i}, Kimmo Kontula^a, Camilla Schalin-Jäntti<sup>a, h

a</sup>Department of Medicine and Research Program in Molecular Medicine, University of Helsinki, Helsinki;
^bDepartment of Medical Biochemistry, University of Kuopio, Kuopio;
^cInstitute of Biomedicine, and
^dThe Hospital for Children and Adolescents, University of Helsinki;
^eDepartment of Epidemiology andHealth Promotion, and
^fDepartment of Molecular Medicine, National Public Health Institute;
^gDepartment ofMedical Genetics, and
^hDivision of Endocrinology, Department of Medicine, University of Helsinki, Helsinki, Finland;
ⁱThe Broad Institute, MIT, Boston, Mass., USA

Address of Corresponding Author

Horm Res 2006;66:61-69 (DOI: 10.1159/000093469)

  Key Words

• Melanocortin-4 receptor promoter
• Mutation
• Early-onset obesity
• Nescient helix-loop-helix 2

  Abstract

Background/Aims: Mutations in melanocortin-4 receptor (MC4R) are the most common genetic cause of human obesity. Mutations in MC4R promoter could also underlie obesity, but have so far not been reported. Transcription factor nescient helix-loop-helix 2 (Nhlh2) is a novel obesity candidate gene. We searched for mutations in MC4R promoter and Nhlh2 gene in 152 children with severe early-onset obesity. Lean subjects (n = 447) served as controls. Methods: MC4R promoter and Nhlh2 gene were investigated by sequencing. Gel shifts and reporter gene assays were used to investigate a deletion in MC4R promoter. Mutation carriers were carefully characterised. Weight charts from index patients and relatives were analysed. Results: We identified a deletion, -439delGC, in MC4R promoter in 2 severely obese, unrelated children and their family members, but not in controls. Index patients and mutation-carrying relatives were affected by early-onset obesity, while non-carriers had normal childhood weight development. The deletion is located at a potential Nhlh2-binding site and gel shift assays showed that Nhlh2 binds to this site. No significant differences in mutant compared to wild-type MC4R promoter activities were detected. No mutations were identified in Nhlh2 gene. Conclusion: We report an MC4R promoter mutation, -439delGC, associated with early-onset obesity and show that transcription factor Nhlh2 recognises this site in vitro. Nhlh2 mutations unlikely underlie severe human obesity.

Copyright © 2006 S. Karger AG, Basel

  Author Contacts

Camilla Schalin-Jäntti, MD, PhD
Division of Endocrinology, Department of Medicine
University of Helsinki, Haartmaninkatu 4, P.O. Box 340
FI-00290 Helsinki (Finland)
Tel. +358 9 4717 2589, Fax +358 9 4717 5798, E-Mail camilla.schalin-jantti@hus.fi

  Article Information

Received: October 14, 2005
Accepted: February 20, 2006
Published online: May 19, 2006
Number of Print Pages : 9
Number of Figures : 5, Number of Tables : 2, Number of References : 41