A Novel Homozygous Missense Mutation of Melanocortin-4 Receptor (MC4R) in a Japanese Woman With Severe Obesity

A Novel Homozygous Missense Mutation of Melanocortin-4 Receptor ( MC4R ) in a Japanese Woman With Severe Obesity Hiromasa Kobayashi 1 , Yoshihiro Ogawa 2 , Mitsuyo Shintani 2 , Ken Ebihara 2 , Makiko Shimodahira 1 , Toshio Iwakura 1 , Megumu Hino 3 , Takashi Ishihara 1 , Katsuji Ikekubo 3 , Hiroyuki Kurahachi 1 and Kazuwa Nakao 2 1 Department of Endocrinology, Kobe City General Hospital, Kobe, Japan 2 Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan 3 Department of Nuclear Medicine, Kobe City General Hospital, Kobe, Japan 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. Footnotes Address correspondence and reprint requests to Hiromasa Kobayashi, MD, Department of Endocrinology, Kobe City General Hospital, Minatojimanakamachi, Chuo-ku, Kobe 650-0046, Japan. E-mail: hiromasa_kobayashi{at}medical.general.hp.city.kobe.jp or Yoshihiro Ogawa, MD, PhD, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku Kyoto 606-8507, Japan. E-mail: ogawa{at}kuhp.kyoto-u.ac.jp Received for publication 23 August 2001 and accepted in revised form 4 October 2001. MC4R, melanocortin-4 receptor; α-MSH, α-melanocyte-stimulating hormone; PCR, polymerase chain reaction; POMC, proopiomelanocortin; RFLP, restriction fragment–length polymorphism; TCA, trichloroa