A Two-Base Deletion –439delGC in the Melanocortin-4 Receptor Promoter Associated with Early-Onset Obesity

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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.

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The identification of potential regulatory motifs in new sequence data is increasingly important for experimental design. Those motifs are commonly located by matches to IUPAC strings derived from consensus sequences. Although this method is simple and widely used, a major drawback of IUPAC strings is that they necessarily remove much of the information originally present in the set of sequences. Nucleotide distribution matrices retain most of the information and are thus better suited to evaluate new potential sites. However, sufficiently large libraries of pre-compiled matrices are a prerequisite for practical application of any matrix-based approach and are just beginning to emerge. Here we present a set of tools for molecular biologists that allows generation of new matrices and detection of potential sequence matches by automatic searches with a library of pre-compiled matrices. We also supply a large library (> 200) of transcription factor binding site matrices that has been compiled on the basis of published matrices as well as entries from the TRANSFAC database, with emphasis on sequences with experimentally verified binding capacity. Our search method includes position weighting of the matrices based on the information content of individual positions and calculates a relative matrix similarity. We show several examples suggesting that this matrix similarity is useful in estimating the functional potential of matrix matches and thus provides a valuable basis for designing appropriate experiments.

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Cornelis Murre, Patrick McCaw, David Baltimore (1989)

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Author and article information

Journal

Journal ID (publisher-id): HRE

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2006

Publication date (Print): July 2006

Publication date (Electronic): 26 July 2006

Volume: 66

Issue: 2

Pages: 61-69

Affiliations

^aDepartment 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

Article

Publisher ID: 93469 Other ID: Horm Res 2006;66:61–69

DOI: 10.1159/000093469

PubMed ID: 16710097

SO-VID: d535d182-3486-47ee-be72-18fb34940467

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