Mutation analysis of the MCHR1 gene in human obesity
| Autor: | Frank Geller, John E. Blundell, Kathrin Reichwald, Gerald Preibisch, Anke Hinney, Matthias Platzer, Heiko Krude, Thomas Gudermann, Hanspeter Goldschmidt, Oluf Pedersen, Karine Clément, H-Erich Wichmann, Claudia Hess, Weidong Li, Klaus Huse, Martin Wabitsch, Lesli H. Larsen, Helmut Schäfer, Arne Astrup, Cornelia Platzer, Anne-Kathrin Wermter, Heike Biebermann, Thorkild I. A. Sørensen, Johannes Hebebrand, Thomas Illig, R. Arlen Price, Thomas R. H. Büch, Caren Vollmert, Helmut Remschmidt, Delphine Eberlé, Wolfgang Siegfried |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Adult
Male Adolescent Sequence analysis Endocrinology Diabetes and Metabolism Inositol Phosphates Medizin Single-nucleotide polymorphism Biology Polymerase Chain Reaction Polymorphism Single Nucleotide Endocrinology Chlorocebus aethiops Cyclic AMP Coding region Animals Humans Obesity Receptors Pituitary Hormone Allele Gene Polymorphism Single-Stranded Conformational Genetic association Genetics Reporter gene Haplotype General Medicine DNA Sequence Analysis DNA Molecular biology COS Cells Female Mitogen-Activated Protein Kinases Polymorphism Restriction Fragment Length |
| Zdroj: | Eur. J. Endocrinol. 152, 851-862 (2005) |
| Popis: | Objective: The importance of the melanin-concentrating hormone (MCH) system for regulation of energy homeostasis and body weight has been demonstrated in rodents. We analysed the human MCH receptor 1 gene (MCHR1) with respect to human obesity.Design: This consisted of genomic screening of 13.4 kb encompassing theMCHR1in extremely obese German children and adolescents and association analyses for two coding single nucleotide polymorphisms (SNPs). To confirm initial positive association results, additional association studies and transmission disequilibrium tests in further German, Danish, French and American samples were conducted. Selected SNPs were investigated using functionalin vitrostudies and reporter gene assays.Methods: Single-stranded conformation polymorphism analysis, re-sequencing, PCR-restriction fragment length polymorphism analyses, tetra-primer amplification refractory mutation systems, matrix-assisted laser desorption/ionization time of flight mass spectrometry and reporter gene assays were carried out as well as measuring inositol phosphate formation, inhibition of cAMP formation and activation of p42/44 MAP kinase.Results: We identified 11 infrequent variations and two SNPs in theMCHR1coding sequence and 18 SNPs (eight novel) in the flanking sequence. Association and transmission disequilibrium with obesity were detected for several SNPs in independent study groups of German obese children and adolescents and controls. In two German samples, encompassing 4056 and 295 individuals, trends towards association with obesity were detected. Findings in a second epidemiological German sample and in Danish, French and American samples were negative. Functionalin vitrostudies as well as reporter gene assays revealed no significant results.Conclusion: Our initial association ofMCHR1alleles/haplotype detected might be related to juvenile-onset obesity, conditional on a particular genetic and/or environmental background. Alternatively, we could not exclude the possibility that the initially detected association represented a false positive finding. |
| Databáze: | OpenAIRE |
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