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Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects

Authors
 Hidekazu Nishigori  ;  Hideaki Tomura  ;  Naoko Tonooka  ;  Masao Kanamori  ;  Shirou Yamada  ;  Kimie Sho  ;  Ituro Inoue  ;  Nobuyuki Kikuchi  ;  Kazumichi Onigata  ;  Itaru Kojima  ;  Tomoko Kohama  ;  Kazuya Yamagata  ;  Qin Yang  ;  Yuji Matsuzawa  ;  Takashi Miki  ;  Susumu Seino  ;  Mi-Young Kim  ;  Hueng-Sik Choi  ;  Yoon-Kwang Lee  ;  David D. Moore  ;  Jun Takeda 
Citation
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.98(2) : 575-580, 2001 
Journal Title
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 
ISSN
 0027-8424 
Issue Date
2001
MeSH
Adolescent ; Adult ; Age of Onset ; Amino Acid Substitution ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Birth Weight/genetics ; Body Weight/genetics ; Child ; Chromosomes, Human, Pair 1/genetics ; Comorbidity ; DNA Mutational Analysis ; DNA-Binding Proteins* ; Diabetes Mellitus, Type 2/epidemiology ; Diabetes Mellitus, Type 2/ethnology ; Diabetes Mellitus, Type 2/genetics* ; Female ; Gene Expression Regulation ; Genes, Dominant ; Genes, Recessive ; Genetic Predisposition to Disease ; Hepatocyte Nuclear Factor 4 ; Heterozygote ; Humans ; Hyperinsulinism/epidemiology ; Hyperinsulinism/ethnology ; Hyperinsulinism/genetics ; Japan/epidemiology ; Lod Score ; Male ; Middle Aged ; Mutation, Missense ; Obesity/epidemiology ; Obesity/ethnology ; Obesity/genetics* ; Pedigree ; Phosphoproteins/physiology ; Point Mutation ; Polymorphism, Genetic ; Receptors, Cytoplasmic and Nuclear/genetics* ; Transcription Factors/physiology ; Transcriptional Activation ; Transfection ; Tumor Cells, Cultured
Abstract
Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4α, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P = 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese.
Files in This Item:
T200103849.pdf Download
DOI
10.1073/pnas.98.2.575
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Choi, Hong Shik(최홍식)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/143184
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