Melanocortin-4 receptor gene:: Case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity

被引:166
作者
Hinney, A
Hohmann, S
Geller, F
Vogel, C
Hess, C
Wermter, AK
Brokamp, B
Goldschmidt, H
Siegfried, W
Remschmidt, H
Schäfer, H
Gudermann, T
Hebebrand, J
机构
[1] Univ Marburg, Dept Child & Adolescent Psychiat, Clin Res Grp, D-35039 Marburg, Germany
[2] Univ Marburg, Dept Pharmacol & Toxicol, D-35033 Marburg, Germany
[3] Univ Marburg, Inst Med Biometry & Epidemiol, D-35037 Marburg, Germany
[4] Spessart Klin, D-63619 Bad Orb, Germany
[5] Obes Treatment Ctr Insula, D-83489 Berchtesgaden, Germany
关键词
D O I
10.1210/jc.2003-030233
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; five of these have not been observed previously. In vitro assays revealed that nine [the haplotype (Y35X; D37V) was counted as one mutation] of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor function. The association test based on functionally relevant mutations was positive (P = 0.006, Fisher's exact test, one-sided). We proceeded by screening a total of 1040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (P = 0.033; exact one-sided McNemar test). These results support the hypothesis that these MC4R mutations represent major gene effects for obesity.
引用
收藏
页码:4258 / 4267
页数:10
相关论文
共 31 条
[1]   The human intronless melanocortin 4-receptor gene is NMD insensitive [J].
Brocke, KS ;
Neu-Yilik, G ;
Gehring, NH ;
Hentze, MW ;
Kulozik, AE .
HUMAN MOLECULAR GENETICS, 2002, 11 (03) :331-335
[2]   Haplosufficiency of the melanocortin-4 receptor gene in individuals with deletions of 18q [J].
Cody, JD ;
Reveles, XT ;
Hale, DE ;
Lehman, D ;
Coon, H ;
Leach, RJ .
HUMAN GENETICS, 1999, 105 (05) :424-427
[3]  
del Giudice EM, 2002, INT J OBESITY, V26, P647, DOI [10.1038/sj.ijo.0801983, 10.1038/sj/ijo/0801983]
[4]   Mutational analysis of melanocortin-4 receptor, agouti-related protein, and α-melanocyte-stimulating hormone genes in severely obese children [J].
Dubern, B ;
Clément, K ;
Pelloux, V ;
Froguel, P ;
Girardet, JP ;
Guy-Grand, B ;
Tounian, P .
JOURNAL OF PEDIATRICS, 2001, 139 (02) :204-209
[5]   Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency [J].
Farooqi, IS ;
Yeo, GSH ;
Keogh, JM ;
Aminian, S ;
Jebb, SA ;
Butler, G ;
Cheetham, T ;
O'Rahilly, S .
JOURNAL OF CLINICAL INVESTIGATION, 2000, 106 (02) :271-279
[6]   Molecular screening of the human melanocortin-4 receptor gene: Identification of a missense variant showing no association with obesity, plasma glucose, or insulin [J].
Gotoda, T ;
Scott, J ;
Aitman, TJ .
DIABETOLOGIA, 1997, 40 (08) :976-979
[7]   Identification and functional analysis of novel human melanocortin-4 receptor variants [J].
Gu, W ;
Tu, ZM ;
Kleyn, PW ;
Kissebah, A ;
Duprat, L ;
Lee, J ;
Chin, W ;
Maruti, S ;
Deng, NH ;
Fisher, SL ;
Franco, LS ;
Burn, P ;
Yagaloff, KA ;
Nathan, J ;
Heymsfield, S ;
Albu, J ;
Pi-Sunyer, FX ;
Allison, DB .
DIABETES, 1999, 48 (03) :635-639
[8]   Epidemic obesity: are genetic factors involved via increased rates of assortative mating? [J].
Hebebrand, J ;
Wulftange, H ;
Goerg, T ;
Ziegler, A ;
Hinney, A ;
Barth, N ;
Mayer, H ;
Remschmidt, H .
INTERNATIONAL JOURNAL OF OBESITY, 2000, 24 (03) :345-353
[9]  
Hebebrand J, 1996, INT J EAT DISORDER, V19, P359, DOI 10.1002/(SICI)1098-108X(199605)19:4&lt
[10]  
359::AID-EAT4&gt