Clinical and functional relevance of melanocortin-4 receptor variants in obese german children

Hormone Research in Paediatrics

Volumn 78, Issue 4, 2012, Pages 237-246

  Melchior, Christin ^a   Schulz, Angela ^a,b   Windholz, Jan ^b   Kiess, Wieland ^b   Schneberg, Torsten ^a   Krner, Antje ^b  

^a Institute of Biochemistry   (Germany)

^b UNIVERSITY HOSPITAL LEIPZIG   (Germany)

Author keywords

Children; Early onset obesity; G protein coupled receptor; Melanocortin 4 receptor; Metabolic syndrome; Obesity; Signal transduction

Indexed keywords

ALPHA INTERMEDIN; GENOMIC DNA; HEMOGLOBIN A1C; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; MELANOCORTIN 4 RECEPTOR;

AGE; ANIMAL CELL; ARTICLE; BODY MASS; CASE CONTROL STUDY; CELL STIMULATION; CHILDHOOD OBESITY; DNA SEQUENCE; FEMALE; GAIN OF FUNCTION MUTATION; GENDER; GENE EXPRESSION; GENE FREQUENCY; GENE IDENTIFICATION; GENE MUTATION; GENE SEQUENCE; GENETIC VARIABILITY; GENOTYPE PHENOTYPE CORRELATION; HETEROZYGOTE; HUMAN; IN VITRO STUDY; LOSS OF FUNCTION MUTATION; MAJOR CLINICAL STUDY; MALE; MULTIPLEX LIGATION DEPENDENT PROBE AMPLIFICATION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PUBERTY; WILD TYPE;

ADOLESCENT; AGE OF ONSET; ANIMALS; CASE-CONTROL STUDIES; CERCOPITHECUS AETHIOPS; CHILD; COS CELLS; FEMALE; GENE FREQUENCY; GENETIC PREDISPOSITION TO DISEASE; GENETIC VARIATION; GERMANY; HUMANS; MALE; OBESITY; POLYMORPHISM, SINGLE NUCLEOTIDE; RECEPTOR, MELANOCORTIN, TYPE 4; TRANSFECTION;

EID: 84868590030     PISSN: 16632818     EISSN: 16632826     Source Type: Journal    
DOI: 10.1159/000343816     Document Type: Article

References (49)

1. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S: Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003; 348: 1085-1095.
2. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P: Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000; 106: 253-262.
3. Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T: Molecular cloning of a novel melanocortin receptor. J Biol Chem 1993; 268: 8246-8250.
4. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD: Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 1994; 8: 1298-1308.
5. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F: Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131-141.
6. Vaisse C, Clement K, Guy-Grand B, Froguel P: A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998; 20: 113-114.
7. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S: A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 1998; 20: 111-112.
8. Lubrano-Berthelier C, Dubern B, Lacorte JM, Picard F, Shapiro A, Zhang S, Bertrais S, Hercberg S, Basdevant A, Clement K, Vaisse C: Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotypephenotype relationship, and lack of association with binge eating. J Clin Endocrinol Metab 2006; 91: 1811-1818.
9. Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J, Ferron C, Froguel P, Vaisse C: Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 2003; 12: 145-153.
10. Branson R, Potoczna N, Kral JG, Lentes KU, Hoehe MR, Horber FF: Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med 2003; 348: 1096-1103.
11. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O'Rahilly S: Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 2000; 106: 271-279.
12. Hinney A, Bettecken T, Tarnow P, Brumm H, Reichwald K, Lichtner P, Scherag A, Nguyen TT, Schlumberger P, Rief W, Vollmert C, Illig T, Wichmann HE, Schafer H, Platzer M, Biebermann H, Meitinger T, Hebebrand J: Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative populationbased sample and obese adults from Germany. J Clin Endocrinol Metab 2006; 91: 1761-1769.
13. Hinney A, Hohmann S, Geller F, Vogel C, Hess C, Wermter AK, Brokamp B, Goldschmidt H, Siegfried W, Remschmidt H, Schafer H, Gudermann T, Hebebrand J: 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. J Clin Endocrinol Metab 2003; 88: 4258-4267.
14. Larsen LH, Echwald SM, Sorensen TI, Andersen T, Wulff BS, Pedersen O: Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity, J Clin Endocrinol Metab 2005; 90: 219-224.
15. Lubrano-Berthelier C, Cavazos M, Le Stunff C, Haas K, Shapiro A, Zhang S, Bougneres P, Vaisse C: The human MC4R promoter: characterization and role in obesity. Diabetes 2003; 52: 2996-3000.
16. Marti A, Corbalan MS, Forga L, Martinez JA, Hinney A, Hebebrand J: A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population. Int J Obes Relat Metab Disord 2003; 27: 385-388.
17. Rettenbacher E, Tarnow P, Brumm H, Prayer D, Wermter AK, Hebebrand J, Biebermann H, Hinney A, Widhalm K: A novel non-synonymous mutation in the melanocortin-4 receptor gene (MC4R) in a 2-year-old Austrian girl with extreme obesity. Exp Clin Endocrinol Diabetes 2007; 115: 7-12.
18. Valli-Jaakola K, Lipsanen-Nyman M, Oksanen L, Hollenberg AN, Kontula K, Bjorbaek C, Schalin-Jantti C: Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese Finnish children and adults. J Clin Endocrinol Metab 2004; 89: 940-945.
19. Tao YX: Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol 2005; 239: 1-14.
20. Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, Ziegler A, Gerber G, Sina M, Gorg T, Mayer H, Siegfried W, Fichter M, Remschmidt H, Hebebrand J: Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab 1999; 84: 1483-1486.
21. Sina M, Hinney A, Ziegler A, Neupert T, Mayer H, Siegfried W, Blum WF, Remschmidt H, Hebebrand J: Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene. Am J Hum Genet 1999; 65: 1501-1507.
22. Liu G, Zhu H, Dong Y, Podolsky RH, Treiber FA, Snieder H: Influence of common variants in FTO and near INSIG2 and MC4R on growth curves for adiposity in African-and European-American youth. Eur J Epidemiol 2011; 26: 463-473.
23. Nijenhuis WA, Garner KM, van Rozen RJ, Adan RA: Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity. J Biol Chem 2003; 278: 22939-22945.
24. Yeo GS, Lank EJ, Farooqi IS, Keogh J, Challis BG, O'Rahilly S: Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 2003; 12: 561-574.
25. Tao YX, Segaloff DL: Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology 2003; 144: 4544-4551.
26. Scherag A, Jarick I, Grothe J, Biebermann H, Scherag S, Volckmar AL, Vogel CI, Greene B, Hebebrand J, Hinney A: Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus. PLoS One 2010; 5:e13967.
27. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Lango Allen H, Lindgren CM, Luan J, Mägi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segrè AV, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, Kilpeläinen TO, Yang J, Bouatia-Naji N, Esko T, Feitosa MF, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben KK, Absher DM, Amin N, Dixon AL, Fisher E, Glazer NL, Goddard ME, Heard-Costa NL, Hoesel V, Hottenga JJ, Johansson A, Johnson T, Ketkar S, Lamina C, Li S, Moffatt MF, Myers RH, Narisu N, Perry JR, Peters MJ, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott LJ, Timpson NJ, Tyrer JP, van Wingerden S, Watanabe RM, White CC, Wiklund F, Barlassina C, Chasman DI, Cooper MN, Jansson JO, Lawrence RW, Pellikka N, Prokopenko I, Shi J, Thiering E, Alavere H, Alibrandi MT, Almgren P, Arnold AM, Aspelund T, Atwood LD, Balkau B, Balmforth AJ, Bennett AJ, Ben-Shlomo Y, Bergman RN, Bergmann S, Biebermann H, Blakemore AI, Boes T, Bonnycastle LL, Bornstein SR, Brown MJ, Buchanan TA, Busonero F, Campbell H, Cappuccio FP, Cavalcanti-Proença C, Chen YD, Chen CM, Chines PS, Clarke R, Coin L, Connell J, Day IN, den Heijer M, Duan J, Ebrahim S, Elliott P, Elosua R, Eiriksdottir G, Erdos MR, Eriksson JG, Facheris MF, Felix SB, Fischer-Posovszky P, Folsom AR, Friedrich N, Freimer NB, Fu M, Gaget S, Gejman PV, Geus EJ, Gieger C, Gjesing AP, Goel A, Goyette P, Grallert H, Grässler J, Greenawalt DM, Groves CJ, Gudnason V, Guiducci C, Hartikainen AL, Hassanali N, Hall AS, Havulinna AS, Hayward C, Heath AC, Hengstenberg C, Hicks AA, Hinney A, Hofman A, Homuth G, Hui J, Igl W, Iribarren C, Isomaa B, Jacobs KB, Jarick I, Jewell E, John U, Jørgensen T, Jousilahti P, Jula A, Kaakinen M, Kajantie E, Kaplan LM, Kathiresan S, Kettunen J, Kinnunen L, Knowles JW, Kolcic I, König IR, Koskinen S, Kovacs P, Kuusisto J, Kraft P, Kvaløy K, Laitinen J, Lantieri O, Lanzani C, Launer LJ, Lecoeur C, Lehtimäki T, Lettre G, Liu J, Lokki ML, Lorentzon M, Luben RN, Ludwig B; MAGIC, Manunta P, Marek D, Marre M, Martin NG, McArdle WL, McCarthy A, McKnight B, Meitinger T, Melander O, Meyre D, Midthjell K, Montgomery GW, Morken MA, Morris AP, Mulic R, Ngwa JS, Nelis M, Neville MJ, Nyholt DR, O'Donnell CJ, O'Rahilly S, Ong KK, Oostra B, Paré G, Parker AN, Perola M, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Rafelt S, Raitakari O, Rayner NW, Ridderstråle M, Rief W, Ruokonen A, Robertson NR, Rzehak P, Salomaa V, Sanders AR, Sandhu MS, Sanna S, Saramies J, Savolainen MJ, Scherag S, Schipf S, Schreiber S, Schunkert H, Silander K, Sinisalo J, Siscovick DS, Smit JH, Soranzo N, Sovio U, Stephens J, Surakka I, Swift AJ, Tammesoo ML, Tardif JC, Teder-Laving M, Teslovich TM, Thompson JR, Thomson B, Tönjes A, Tuomi T, van Meurs JB, van Ommen GJ, Vatin V, Viikari J, Visvikis-Siest S, Vitart V, Vogel CI, Voight BF, Waite LL, Wallaschofski H, Walters GB, Widen E, Wiegand S, Wild SH, Willemsen G, Witte DR, Witteman JC, Xu J, Zhang Q, Zgaga L, Ziegler A, Zitting P, Beilby JP, Farooqi IS, Hebebrand J, Huikuri HV, James AL, Kähönen M, Levinson DF, Macciardi F, Nieminen MS, Ohlsson C, Palmer LJ, Ridker PM, Stumvoll M, Beckmann JS, Boeing H, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Collins FS, Cupples LA, Smith GD, Erdmann J, Froguel P, Grönberg H, Gyllensten U, Hall P, Hansen T, Harris TB, Hattersley AT, Hayes RB, Heinrich J, Hu FB, Hveem K, Illig T, Jarvelin MR, Kaprio J, Karpe F, Khaw KT, Kiemeney LA, Krude H, Laakso M, Lawlor DA, Metspalu A, Munroe PB, Ouwehand WH, Pedersen O, Penninx BW, Peters A, Pramstaller PP, Quertermous T, Reinehr T, Rissanen A, Rudan I, Samani NJ, Schwarz PE, Shuldiner AR, Spector TD, Tuomilehto J, Uda M, Uitterlinden A, Valle TT, Wabitsch M, Waeber G, Wareham NJ, Watkins H; Procardis Consortium, Wilson JF, Wright AF, Zillikens MC, Chatterjee N, McCarroll SA, Purcell S, Schadt EE, Visscher PM, Assimes TL, Borecki IB, Deloukas P, Fox CS, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, Mohlke KL, O'Connell JR, Peltonen L, Schlessinger D, Strachan DP, van Duijn CM, Wichmann HE, Frayling TM, Thorsteinsdottir U, Abecasis GR, Barroso I, Boehnke M, Stefansson K, North KE, McCarthy MI, Hirschhorn JN, Ingelsson E, Loos RJ: Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937-948.
28. Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, Lettre G, Lim N, Lyon HN, McCarroll SA, Papadakis K, Qi L, Randall JC, Roccasecca RM, Sanna S, Scheet P, Weedon MN, Wheeler E, Zhao JH, Jacobs LC, Prokopenko I, Soranzo N, Tanaka T, Timpson NJ, Almgren P, Bennett A, Bergman RN, Bingham SA, Bonnycastle LL, Brown M, Burtt NP, Chines P, Coin L, Collins FS, Connell JM, Cooper C, Smith GD, Dennison EM, Deodhar P, Elliott P, Erdos MR, Estrada K, Evans DM, Gianniny L, Gieger C, Gillson CJ, Guiducci C, Hackett R, Hadley D, Hall AS, Havulinna AS, Hebebrand J, Hofman A, Isomaa B, Jacobs KB, Johnson T, Jousilahti P, Jovanovic Z, Khaw KT, Kraft P, Kuokkanen M, Kuusisto J, Laitinen J, Lakatta EG, Luan J, Luben RN, Mangino M, McArdle WL, Meitinger T, Mulas A, Munroe PB, Narisu N, Ness AR, Northstone K, O'Rahilly S, Purmann C, Rees MG, Ridderstråle M, Ring SM, Rivadeneira F, Ruokonen A, Sandhu MS, Saramies J, Scott LJ, Scuteri A, Silander K, Sims MA, Song K, Stephens J, Stevens S, Stringham HM, Tung YC, Valle TT, Van Duijn CM, Vimaleswaran KS, Vollenweider P, Waeber G, Wallace C, Watanabe RM, Waterworth DM, Watkins N; Wellcome Trust Case Control Consortium, Witteman JC, Zeggini E, Zhai G, Zillikens MC, Altshuler D, Caulfield MJ, Chanock SJ, Farooqi IS, Ferrucci L, Guralnik JM, Hattersley AT, Hu FB, Jarvelin MR, Laakso M, Mooser V, Ong KK, Ouwehand WH, Salomaa V, Samani NJ, Spector TD, Tuomi T, Tuomilehto J, Uda M, Uitterlinden AG, Wareham NJ, Deloukas P, Frayling TM, Groop LC, Hayes RB, Hunter DJ, Mohlke KL, Peltonen L, Schlessinger D, Strachan DP, Wichmann HE, McCarthy MI, Boehnke M, Barroso I, Abecasis GR, Hirschhorn JN; Genetic Investigation of ANthropometric Traits Consortium: Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41: 25-34.
29. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI; Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM; KORA, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O'Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L; Nurses' Health Study, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK; Diabetes Genetics Initiative, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M; SardiNIA Study, Vogel CI, Wallace C, Waterworth DM, Weedon MN; Wellcome Trust Case Control Consortium, Willer CJ; FUSION, Wraight, Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Jacobs KB, Chanock SJ, Hayes RB, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M, Mohlke KL: Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 2008; 40: 768-775.
30. Loos RJ: The genetic epidemiology of melanocortin 4 receptor variants. Eur J Pharmacol 2011; 660: 156-164.
31. Körner A, Berndt J, Stumvoll M, Kiess W, Kovacs P: TCF7L2 gene polymorphisms confer an increased risk for early impairment of glucose metabolism and increased height in obese children. J Clin Endocrinol Metab 2007; 92: 1956-1960.
32. Kromeyer-Hauschild K, Zellner K: Trends in overweight and obesity and changes in the distribution of body mass index in schoolchildren of Jena, East Germany. Eur J Clin Nutr 2007; 61: 404-411.
33. Stutzmann F, Vatin V, Cauchi S, Morandi A, Jouret B, Landt O, Tounian P, Levy-Marchal C, Buzzetti R, Pinelli L, Balkau B, Horber F, Bougneres P, Froguel P, Meyre D: Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum Mol Genet 2007; 16: 1837-1844.
34. Xi B, Wang C, Wu L, Zhang M, Shen Y, Zhao X, Wang X, Mi J: Influence of physical inactivity on associations between single nucleotide polymorphisms and genetic predisposition to childhood obesity. Am J Epidemiol 2011; 173: 1256-1262.
35. Stäubert C, Tarnow P, Brumm H, Pitra C, Gudermann T, Grüters A, Schöneberg T, Biebermann H, Römpler H: Evolutionary aspects in evaluating mutations in the melanocortin 4 receptor. Endocrinology 2007; 148: 4642-4648.
36. Cody JD, Reveles XT, Hale DE, Lehman D, Coon H, Leach RJ: Haplosufficiency of the melancortin-4 receptor gene in individuals with deletions of 18q. Hum Genet 1999; 105: 424-427.
37. Schöneberg T, Schulz A, Biebermann H, Grüters A, Grimm T, Hubschmann K, Filler G, Gudermann T, Schultz G: V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms. Hum Mutat 1998; 12: 196-205.
38. Rutanen J, Pihlajamaki J, Karhapaa P, Vauhkonen I, Kuusisto J, Moilanen ML, Laakso M: The Val103Ile polymorphism of melanocortin-4 receptor regulates energy expenditure and weight gain. Obes Res 2004; 12: 1060-1066.
39. Gu W, Tu Z, Kleyn PW, Kissebah A, Duprat L, Lee J, Chin W, Maruti S, Deng N, Fisher SL, Franco LS, Burn P, Yagaloff KA, Nathan J, Heymsfield S, Albu J, Pi-Sunyer FX, Allison DB: Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 1999; 48: 635-639.
40. Reinehr T, Hebebrand J, Friedel S, Toschke AM, Brumm H, Biebermann H, Hinney A: Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity (Silver Spring) 2009; 17: 382-389.
41. Wang D, Ma J, Zhang S, Hinney A, Hebebrand J, Wang Y, Wang HJ: Association of the MC4R V103I polymorphism with obesity: a Chinese case-control study and metaanalysis in 55,195 individuals. Obesity (Silver Spring) 2010; 18: 573-579.
42. Melchior C, Kiess W, Dittrich K, Schulz A, Schoneberg T, Korner A: Slim despite a genetic predisposition for obesity -influence of environmental factors as chance? A case report (in German). Dtsch Med Wochenschr 2009; 134: 1047-1050.
43. Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, Astruc B, Mayer JP, Brage S, See TC, Lomas DJ, O'Rahilly S, Farooqi IS: Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med 2009; 360: 44-52.
44. Young EH, Wareham NJ, Farooqi S, Hinney A, Hebebrand J, Scherag A, O'Rahilly S, Barroso I, Sandhu MS: The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals. Int J Obes (Lond) 2007; 31: 1437-1441.
45. Perez-Martinez P, Garcia-Rios A, Delgado-Lista J, Delgado-Casado N, Malagon MM, Marin C, Gomez-Luna P, Caballero J, Perez-Jimenez F, Lopez-Miranda J: A variant near the melanocortin-4 receptor gene regulates postprandial lipid metabolism in a healthy Caucasian population. Br J Nutr 2011; 106: 468-471.
46. Xiang Z, Litherland SA, Sorensen NB, Proneth B, Wood MS, Shaw AM, Millard WJ, Haskell-Luevano C: Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin- derived agonists and the agouti-related protein (AGRP) antagonist. Biochemistry 2006; 45: 7277-7288.
47. Hinney A, Hohmann S, Geller F, Vogel C, Hess C, Wermter AK, Brokamp B, Goldschmidt H, Siegfried W, Remschmidt H, Schafer H, Gudermann T, Hebebrand J: 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. J Clin Endocrinol Metab 2003; 88: 4258-4267.
48. Biebermann H, Krude H, Elsner A, Chubanov V, Gudermann T, Gruters A: Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization. Diabetes 2003; 52: 2984-2988.
49. Tao YX, Segaloff DL: Functional analyses of melanocortin-4 receptor mutations identified from patients with binge eating disorder and nonobese or obese subjects. J Clin Endocrinol Metab 2005; 90: 5632-5638.