title: Melanin-concentrating hormone receptor mutations and human obesity: functional analysis.
abstract: Melanin-concentrating hormone (MCH), a neuropeptide highly expressed in the lateral hypothalamus, has an important role in the regulation of energy balance and body weight in rodents. We examined whether mutations in the two known MCH receptors might be associated with obesity-related phenotypes in humans. Among 106 subjects with severe early onset obesity and a history of hyperphagia, we found two missense variants in MCHR1: Y181H and R248Q. Neither of these was found in 192 normal weight controls. R248Q cosegregated with obesity across two generations; family data were unavailable for Y181H. When expressed in HEK293 cells, R248Q showed no evidence of constitutive activation or ligand hypersensitivity for extracellular signal-regulated kinase phosphorylation. In addition, R248Q showed no enhanced suppression of cAMP generation. Two common single-nucleotide polymorphisms were found to be in linkage disequilibrium: g.-114A>G and c.39C>T. No association between either of these single-nucleotide polymorphisms and obesity-related phenotypes was found among a population cohort of 541 whites. Only two rare noncoding variants were found in MCHR2. In conclusion, mutations in the MCH receptors are not commonly found in humans with severe early onset obesity. Clarification of the relationship of these variants to obesity must await study in other populations and/or in genetically modified mice.
authors.affiliation: University Department of Clinical Biochemistry, Cambridge Institute of medical Research, Cambridge United Kingdom.
authors.forename: William T
authors.initials: WT
authors.lastname: Gibson
authors.forename: Pavlos
authors.initials: P
authors.lastname: Pissios
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Trombly
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.forename: Julia
authors.initials: J
authors.lastname: Keogh
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D006963:Hyperphagia / Q000235:genetics; D015810:Linkage Disequilibrium; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled; D011979:Receptors, Pituitary Hormone / Q000737:chemistry / Q000235:genetics*
chemical_list: C431280:MCHR2 protein, human; D043562:Receptors, G-Protein-Coupled; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins