title: A Novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity.
abstract: The melanocortin-4 receptor (MC4R) is a member of the seven membrane-spanning G protein-coupled receptor superfamily and signals through the activation of adenylyl cyclase. The MC4R mutations are the most common known monogenic cause of human obesity. However, no such mutations have been found in Japanese obese subjects. Here we report a novel homozygous missense mutation of MC4R (G98R) in a nondiabetic Japanese woman with severe early-onset obesity, which is located in its second transmembrane domain. Her birth weight was 3,360 g, and she gained weight progressively from 10 months of age. At 40 years of age, her weight reached 160 kg and a BMI of 62 kg/m(2). Her parents, who are heterozygous for the mutation, have BMIs of 26 and 27 kg/m(2). In vitro transient transfection assays revealed no discernable agonist ligand binding and cAMP production in HEK293 cells expressing the mutant receptor, indicating a severe loss-of-function mutation. This study represents the first demonstration of a pathogenic mutation of MC4R in Japan and will provide further insight into the pathophysiologic role of the hypothalamic melanocortin system in human obesity.
authors.affiliation: Department of Endocrinology, Kobe City General Hospital, Kobe, Japan. hirmasa_kobayashi@medical.general.hp.city.kobe.jp
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Shintani
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimodahira
authors.forename: Toshio
authors.initials: T
authors.lastname: Iwakura
authors.forename: Megumu
authors.initials: M
authors.lastname: Hino
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishihara
authors.forename: Katsuji
authors.initials: K
authors.lastname: Ikekubo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kurahachi
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003062:Codon / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D007564:Japan; D020738:Leptin / Q000097:blood; D008297:Male; D020125:Mutation, Missense; D009767:Obesity, Morbid / Q000235:genetics*; D010375:Pedigree; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values; D014162:Transfection; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D003062:Codon; D020738:Leptin; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide; D011994:Recombinant Proteins; D000521:alpha-MSH