title: Studies of the neuromedin U-2 receptor gene in human obesity: evidence for the existence of two ancestral forms of the receptor.
abstract: Central administration of neuromedin U (NMU) suppresses food intake acting through the NMU-2 receptor (NMU2R), which is expressed in the hypothalamus. We screened the NMU2R gene in 96 patients with severe early-onset obesity. A common variant haplotype was found (f-0.21). This common variant haplotype was unusual in nature, consisting of four non-contiguous missense changes in complete linkage disequilibrium, and across two separate exons. The variant haplotype resulted in four amino acid substitutions (S295T/F312L/P380L/ M385 V) and was present in several other Europid populations and in subjects of South Asian, East Asian and African American origin, but not in eleven African Pygmies. This variant haplotype was not associated with obesity or related traits in 500 subjects from a prospective population-based cohort. In summary, we have identified two markedly different isoforms of the NMU-2 receptor, presumably arising through an ancient and complex mutational event; no genetic associations between this haplotype and obesity-related traits were, however, discerned. Further investigation of the pharmacogenomic consequences of NMU2R variation in humans is warranted.
authors.affiliation: University of Cambridge, Department of Medicine, Box 232, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Julia
authors.initials: J
authors.lastname: Keogh
authors.forename: Carl
authors.initials: C
authors.lastname: Montague
authors.forename: John
authors.initials: J
authors.lastname: Brennand
authors.forename: Lynn
authors.initials: L
authors.lastname: Jorde
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019143:Evolution, Molecular; D006239:Haplotypes; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D015810:Linkage Disequilibrium; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011446:Prospective Studies; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D008565:Membrane Proteins; D020033:Protein Isoforms; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor