TY - JOUR
T1 - A novel homozygous missence mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with obesity
AU - Kobayashi, Hiromasa
AU - Ogawa, Yoshihiro
AU - Shintani, Mitsuyo
AU - Ebihara, Ken
AU - Shimodahira, Makiko
AU - Iwakura, Toshio
AU - Hino, Megumu
AU - Ishihara, Takashi
AU - Ikekubo, Katsuji
AU - Kurahachi, Hiroyuki
AU - Nakao, Kazuwa
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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/m2. Her parents, who are heterozygous for the mutation, have BMIs of 26 and 27 kg/m2. 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.
AB - 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/m2. Her parents, who are heterozygous for the mutation, have BMIs of 26 and 27 kg/m2. 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.
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U2 - 10.2337/diabetes.51.1.243
DO - 10.2337/diabetes.51.1.243
M3 - Article
C2 - 11756348
AN - SCOPUS:0036094522
VL - 51
SP - 243
EP - 246
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 1
ER -