title: Mutation analysis of the MCHR1 gene in human obesity.
abstract: 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.
  
  
  METHODS
  This consisted of genomic screening of 13.4 kb encompassing the MCHR1 in 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 functional in vitro studies 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 the MCHR1 coding 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. Functional in vitro studies as well as reporter gene assays revealed no significant results.
  
  
  CONCLUSIONS
  Our initial association of MCHR1 alleles/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.
authors.affiliation: Clinical Research Group, Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Wermter
authors.forename: Kathrin
authors.initials: K
authors.lastname: Reichwald
authors.forename: Thomas
authors.initials: T
authors.lastname: Büch
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.forename: Cornelia
authors.initials: C
authors.lastname: Platzer
authors.forename: Klaus
authors.initials: K
authors.lastname: Huse
authors.forename: Claudia
authors.initials: C
authors.lastname: Hess
authors.forename: Helmut
authors.initials: H
authors.lastname: Remschmidt
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Gerald
authors.initials: G
authors.lastname: Preibisch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Siegfried
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Goldschmidt
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Li
authors.forename: R Arlen
authors.initials: RA
authors.lastname: Price
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Caren
authors.initials: C
authors.lastname: Vollmert
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Thorkild I A
authors.initials: TI
authors.lastname: Sørensen
authors.forename: Arne
authors.initials: A
authors.lastname: Astrup
authors.forename: Lesli Hingstrup
authors.initials: LH
authors.lastname: Larsen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Delphine
authors.initials: D
authors.lastname: Eberlé
authors.forename: Karine
authors.initials: K
authors.lastname: Clément
authors.forename: John
authors.initials: J
authors.lastname: Blundell
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Helmut
authors.initials: H
authors.lastname: Schäfer
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D011979:Receptors, Pituitary Hormone / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D007295:Inositol Phosphates; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; D004247:DNA; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases