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Pediatric Obesity pp 135–152Cite as

Monogenic Obesity

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Part of the book series: Contemporary Endocrinology ((COE))

Abstract

The global increase in the prevalence of childhood obesity is attributed to recent changes in the environment (easy access to high-energy palatable food, combined with decreased physical activity). However, individual differences in obesity risk are mainly attributed to genetic variations. Being a complex heritable disorder, obesity results from the interplay between genetic susceptibility and the environment. Investigations exploring the genetic basis of obesity have identified numerous genes associated with syndromic, monogenic, oligogenic, and polygenic obesity. In this chapter, we comprehensively review 12 monogenic/oligogenic childhood obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin and directly related molecular pathways. Furthermore, we provide a clinical genetic testing strategy in order to improve the management of children with early-onset severe forms of obesity and discuss the development of new drugs that bypass the leptin signal.

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References

  1. Organization WH. Obesity and overweight: World Health Organization; 2015.

    Google Scholar 

  2. Lobstein T, Jackson-Leach R. Planning for the worst: estimates of obesity and comorbidities in school-age children in 2025. Pediatr Obes. 2016;11(5):321–5.

    Article  CAS  PubMed  Google Scholar 

  3. Han JC, Lawlor DA, Kimm SY. Childhood obesity. Lancet (London, England). 2010;375(9727):1737–48.

    Article  Google Scholar 

  4. Patro B, Liber A, Zalewski B, Poston L, Szajewska H, Koletzko B. Maternal and paternal body mass index and offspring obesity: a systematic review. Ann Nutr Metab. 2013;63(1–2):32–41.

    Article  CAS  PubMed  Google Scholar 

  5. Wardle J, Carnell S, Haworth CM, Plomin R. Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr. 2008;87(2):398–404.

    CAS  PubMed  Google Scholar 

  6. Pigeyre M, Yazdi FT, Kaur Y, Meyre D. Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Clin Sci (Lond). 2016;130(12):943–86.

    Article  CAS  Google Scholar 

  7. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387(6636):903–7.

    Article  CAS  PubMed  Google Scholar 

  8. Yazdi FT, Clee SM, Meyre D. Obesity genetics in mouse and human: back and forth, and back again. Peer J. 2015;3:e856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, et al. Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab. 2004;89(10):4821–6.

    Article  CAS  PubMed  Google Scholar 

  10. Fatima W, Shahid A, Imran M, Manzoor J, Hasnain S, Rana S, et al. Leptin deficiency and leptin gene mutations in obese children from Pakistan. Int J Pediatr Obes. 2011;6(5–6):419–27.

    Article  PubMed  Google Scholar 

  11. Saeed S, Bonnefond A, Manzoor J, Philippe J, Durand E, Arshad M, et al. Novel LEPR mutations in obese Pakistani children identified by PCR-based enrichment and next generation sequencing. Obesity. 2014;22(4):1112–7.

    Article  CAS  PubMed  Google Scholar 

  12. Saeed S, Bonnefond A, Manzoor J, Shabir F, Ayesha H, Philippe J, et al. Genetic variants in LEP, LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population. Obesity (Silver Spring). 2015;23(8):1687–95.

    Article  CAS  Google Scholar 

  13. Thakur S, Kumar A, Dubey S, Saxena R, Peters AN, Singhal A. A novel mutation of the leptin gene in an Indian patient. Clin Genet. 2014;86(4):391–3.

    Article  CAS  PubMed  Google Scholar 

  14. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18(3):213–5.

    Article  CAS  PubMed  Google Scholar 

  15. Mazen I, El-Gammal M, Abdel-Hamid M, Amr K. A novel homozygous missense mutation of the leptin gene (N103K) in an obese Egyptian patient. Mol Genet Metab. 2009;97(4):305–8.

    Article  CAS  PubMed  Google Scholar 

  16. Fischer-Posovszky P, von Schnurbein J, Moepps B, Lahr G, Strauss G, Barth TF, et al. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. J Clin Endocrinol Metab. 2010;95(6):2836–40. https://doi.org/10.1210/jc.2009-2466.

    Article  CAS  PubMed  Google Scholar 

  17. Wabitsch M, Funcke J-B, Lennerz B, Kuhnle-Krahl U, Lahr G, Debatin K-M, et al. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med. 2015;372(1):48–54.

    Article  PubMed  CAS  Google Scholar 

  18. Wabitsch M, Funcke JB, von Schnurbein J, Denzer F, Lahr G, Mazen I, et al. Severe early-onset obesity due to bioinactive Leptin caused by a p.N103K mutation in the Leptin gene. J Clin Endocrinol Metab. 2015;100(9):3227–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shabana HS. The p. N103K mutation of leptin (LEP) gene and severe early onset obesity in Pakistan. Biol Res. 2016;49:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110(8):1093–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell. 2014;159(6):1404–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, et al. Partial leptin deficiency and human adiposity. Nature. 2001;414(6859):34–5.

    Article  CAS  PubMed  Google Scholar 

  23. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392(6674):398–401.

    Article  PubMed  Google Scholar 

  24. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356(3):237–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Le Beyec J, Cugnet-Anceau C, Pepin D, Alili R, Cotillard A, Lacorte JM, et al. Homozygous leptin receptor mutation due to uniparental disomy of chromosome 1: response to bariatric surgery. J Clin Endocrinol Metab. 2013;98(2):E397–402.

    Article  PubMed  CAS  Google Scholar 

  26. Huvenne H, Le Beyec J, Pépin D, Alili R, Kherchiche PP, Jeannic E, et al. Seven novel deleterious LEPR mutations found in early-onset obesity: a ΔExon6–8 shared by subjects from Reunion Island, France, suggests a founder effect. J Clin Endocrinol Metabol. 2015;100(5):E757–E66.

    Article  CAS  Google Scholar 

  27. Vauthier V, Jaillard S, Journel H, Dubourg C, Jockers R, Dam J. Homozygous deletion of an 80 kb region comprising part of DNAJC6 and LEPR genes on chromosome 1P31.3 is associated with early onset obesity, mental retardation and epilepsy. Mol Genet Metab. 2012;106(3):345–50.

    Article  CAS  PubMed  Google Scholar 

  28. Hannema SE, Wit JM, Houdijk ME, van Haeringen A, Bik EC, Verkerk AJ, et al. Novel Leptin receptor mutations identified in two girls with severe obesity are associated with increased bone mineral density. Horm Res Paediatr. 2016;85(6):412–20.

    Article  CAS  PubMed  Google Scholar 

  29. Mazen I, El-Gammal M, Abdel-Hamid M, Farooqi IS, Amr K. Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity. Mol Genet Metab. 2011;102(4):461–4.

    Article  CAS  PubMed  Google Scholar 

  30. Andiran N, Celik N, Andiran F. Homozygosity for two missense mutations in the leptin receptor gene (P316:W646C) in a Turkmenian girl with severe early-onset obesity. J Pediatr Endocrinol Metab. 2011;24(11–12):1043–5.

    PubMed  Google Scholar 

  31. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19(2):155–7.

    Article  CAS  PubMed  Google Scholar 

  32. Aslan IR, Ranadive SA, Valle I, Kollipara S, Noble JA, Vaisse C. The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus. Int J Obes. 2014;38(1):148–51.

    Article  CAS  Google Scholar 

  33. Clement K, Dubern B, Mencarelli M, Czernichow P, Ito S, Wakamatsu K, et al. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J Clin Endocrinol Metab. 2008;93(12):4955–62. https://doi.org/10.1210/jc.2008-1164.

  34. Samuels ME, Gallo-Payet N, Pinard S, Hasselmann C, Magne F, Patry L, et al. Bioinactive ACTH causing glucocorticoid deficiency. J Clin Endocrinol Metab. 2013;98(2):736–42.

    Article  CAS  PubMed  Google Scholar 

  35. Cirillo G, Marini R, Ito S, Wakamatsu K, Scianguetta S, Bizzarri C, et al. Lack of red hair phenotype in a north-African obese child homozygous for a novel POMC null mutation: nonsense-mediated decay RNA evaluation and hair pigment chemical analysis. Br J Dermatol. 2012;167(6):1393–5.

    Article  CAS  PubMed  Google Scholar 

  36. Hung CN, Poon WT, Lee CY, Law CY, Chan AY. A case of early-onset obesity, hypocortisolism, and skin pigmentation problem due to a novel homozygous mutation in the proopiomelanocortin (POMC) gene in an Indian boy. J Pediatr Endocrinol Metab. 2012;25(1–2):175–9.

    CAS  PubMed  Google Scholar 

  37. Özen S, Özcan N, Uçar SK, Gökşen D, Darcan Ş. Unexpected clinical features in a female patient with proopiomelanocortin (POMC) deficiency. J Pediatr Endocrinol Metab. 2015;28(5–6):691–4.

    PubMed  Google Scholar 

  38. Biebermann H, Castañeda TR, van Landeghem F, von Deimling A, Escher F, Brabant G, et al. A role for β-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab. 2006;3(2):141–6.

    Article  CAS  PubMed  Google Scholar 

  39. Challis BG, Pritchard LE, Creemers JW, Delplanque J, Keogh JM, Luan JA, et al. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet. 2002;11(17):1997–2004.

    Article  CAS  PubMed  Google Scholar 

  40. Dubern B, Lubrano-Berthelier C, Mencarelli M, Ersoy B, Frelut M-L, Bouglé D, et al. Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of a novel deleterious heterozygous mutation located in the alpha-melanocyte stimulating hormone domain. Pediatr Res. 2008;63(2):211–6.

    Article  CAS  PubMed  Google Scholar 

  41. Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka J, Lowenbein S, et al. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes. 2006;55(9):2549–53.

    Article  CAS  PubMed  Google Scholar 

  42. Lee YS, Challis BG, Thompson DA, Yeo GS, Keogh JM, Madonna ME, et al. A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab. 2006;3(2):135–40.

    Article  PubMed  CAS  Google Scholar 

  43. O’Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, White A, et al. Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med. 1995;333(21):1386–90.

    Article  PubMed  Google Scholar 

  44. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson M-L, Sanders L, Montague CT, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997;16(3):303–6.

    Article  CAS  PubMed  Google Scholar 

  45. Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson M-L, Varro A, Dockray GJ, et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Investig. 2003;112(10):1550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Frank GR, Fox J, Candela N, Jovanovic Z, Bochukova E, Levine J, et al. Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency. Mol Genet Metab. 2013;110(1):191–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, Lank E, et al. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metabol. 2007;92(9):3369–73.

    Article  CAS  Google Scholar 

  48. Harter B, Fuchs I, Muller T, Akbulut UE, Cakir M, Janecke AR. Early clinical diagnosis of PC1/3 deficiency in a patient with a novel homozygous PCSK1 splice-site mutation. J Pediatr Gastroenterol Nutr. 2016;62(4):577–80.

    Article  PubMed  CAS  Google Scholar 

  49. Yourshaw M, Solorzano-Vargas RS, Pickett LA, Lindberg I, Wang J, Cortina G, et al. Exome sequencing finds a novel PCSK1 mutation in a child with generalized malabsorptive diarrhea and diabetes insipidus. J Pediatr Gastroenterol Nutr. 2013;57(6):759.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Martín MG, Lindberg I, Solorzano-Vargas RS, Wang J, Avitzur Y, Bandsma R, et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology. 2013;145(1):138–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Philippe J, Stijnen P, Meyre D, De Graeve F, Thuillier D, Delplanque J, et al. A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. Int J Obes. 2015;39(2):295–302.

    Article  CAS  Google Scholar 

  52. Blanco EH, Ramos-Molina B, Lindberg I. Revisiting PC1/3 mutants: dominant-negative effect of endoplasmic reticulum-retained mutants. Endocrinology. 2015;156(10):3625–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Creemers JW, Choquet H, Stijnen P, Vatin V, Pigeyre M, Beckers S, et al. Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity. Diabetes. 2012;61(2):383–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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(12):1085–95.

    Article  CAS  PubMed  Google Scholar 

  55. 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(2):113–4.

    Article  CAS  PubMed  Google Scholar 

  56. 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(2):111–2.

    Article  CAS  PubMed  Google Scholar 

  57. Dubern B, Bisbis S, Talbaoui H, Le Beyec J, Tounian P, Lacorte J-M, et al. Homozygous null mutation of the melanocortin-4 receptor and severe early-onset obesity. J Pediatr. 2007;150(6):613–7e1.

    Article  CAS  PubMed  Google Scholar 

  58. Vollbach H, Brandt S, Lahr G, Denzer C, von Schnurbein J, Debatin KM, et al. Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort. Int J Obes. 2017;41(1):13–22.

    Article  CAS  Google Scholar 

  59. Garg G, Kumar J, McGuigan FE, Ridderstråle M, Gerdhem P, Luthman H, et al. Variation in the MC4R gene is associated with bone phenotypes in elderly Swedish women. PLoS One. 2014;9(2):e88565.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Timpson NJ, Sayers A, Davey-Smith G, Tobias JH. How does body fat influence bone mass in childhood? A Mendelian randomization approach. J Bone Miner Res. 2009;24(3):522–33.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Investig. 2000;106(2):271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Stanikova D, Surova M, Buzga M, Skopkova M, Ticha L, Petrasova M, et al. Age of obesity onset in MC4R mutation carriers. Endocr Regul. 2014;49(3):137–40.

    Article  Google Scholar 

  63. Stutzmann F, Tan K, Vatin V, Dina C, Jouret B, Tichet J, et al. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes. 2008;57(9):2511–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lee YS, Poh LKS, Kek BLK, Loke KY. The role of melanocortin 3 receptor gene in childhood obesity. Diabetes. 2007;56(10):2622–30.

    Article  CAS  PubMed  Google Scholar 

  65. Calton MA, Ersoy BA, Zhang S, Kane JP, Malloy MJ, Pullinger CR, et al. Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large north American case–control study. Hum Mol Genet. 2009;18(6):1140–7.

    Article  CAS  PubMed  Google Scholar 

  66. Mencarelli M, Dubern B, Alili R, Maestrini S, Benajiba L, Tagliaferri M, et al. Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity. Hum Mol Genet. 2011;20(2):392–9.

    Article  CAS  PubMed  Google Scholar 

  67. Zegers D, Beckers S, de Freitas F, Peeters AV, Mertens IL, Verhulst SL, et al. Identification of three novel genetic variants in the melanocortin-3 receptor of obese children. Obesity (Silver Spring). 2011;19(1):152–9. https://doi.org/10.1038/oby.2010.127.

    Article  CAS  Google Scholar 

  68. Yang F, Huang H, Tao YX. Biased signaling in naturally occurring mutations in human melanocortin-3 receptor gene. Int J Biol Sci. 2015;11(4):423–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Asai M, Ramachandrappa S, Joachim M, Shen Y, Zhang R, Nuthalapati N, et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science. 2013;341(6143):275–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chan LF, Webb TR, Chung T-T, Meimaridou E, Cooray SN, Guasti L, et al. MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. Proc Natl Acad Sci. 2009;106(15):6146–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Novoselova TV, Larder R, Rimmington D, Lelliott C, Wynn EH, Gorrigan RJ, et al. Loss of Mrap2 is associated with Sim1 deficiency and increased circulating cholesterol. J Endocrinol. 2016;230(1):13–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Schonnop L, Kleinau G, Herrfurth N, Volckmar AL, Cetindag C, Muller A, et al. Decreased melanocortin-4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene. Obesity (Silver Spring). 2016;24(9):1976–82.

    Article  CAS  Google Scholar 

  73. Geets E, Zegers D, Beckers S, Verrijken A, Massa G, Van Hoorenbeeck K, et al. Copy number variation (CNV) analysis and mutation analysis of the 6q14.1-6q16.3 genes SIM1 and MRAP2 in Prader Willi like patients. Mol Genet Metab. 2016;117(3):383–8.

    Article  CAS  PubMed  Google Scholar 

  74. Bonaglia MC, Ciccone R, Gimelli G, Gimelli S, Marelli S, Verheij J, et al. Detailed phenotype–genotype study in five patients with chromosome 6q16 deletion: narrowing the critical region for Prader–Willi-like phenotype. Eur J Hum Genet. 2008;16(12):1443–9.

    Article  CAS  PubMed  Google Scholar 

  75. Izumi K, Housam R, Kapadia C, Stallings VA, Medne L, Shaikh TH, et al. Endocrine phenotype of 6q16. 1–q21 deletion involving SIM1 and Prader–Willi syndrome-like features. Am J Med Genet A. 2013;161(12):3137–43.

    Article  CAS  Google Scholar 

  76. Villa A, Urioste M, Bofarull JM, Martínez-Frías ML. De novo interstitial deletion q16. 2q21 on chromosome 6. Am J Med Genet. 1995;55(3):379–83.

    Article  CAS  PubMed  Google Scholar 

  77. Stein CK, Stred SE, Thomson LL, Smith FC, Hoo JJ. Interstitial 6q deletion and Prader-Willi-like phenotype. Clin Genet. 1996;49(6):306–10.

    Article  CAS  PubMed  Google Scholar 

  78. El Khattabi L, Guimiot F, Pipiras E, Andrieux J, Baumann C, Bouquillon S, et al. Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1. Eur J Hum Genet. 2015;23(8):1010–8.

    Article  PubMed  CAS  Google Scholar 

  79. Michaud JL, DeRossi C, May NR, Holdener BC, Fan C-M. ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. Mech Dev. 2000;90(2):253–61.

    Article  CAS  PubMed  Google Scholar 

  80. Michaud JL, Rosenquist T, May NR, Fan C-M. Development of neuroendocrine lineages requires the bHLH–PAS transcription factor SIM1. Genes Dev. 1998;12(20):3264–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Michaud JL, Boucher F, Melnyk A, Gauthier F, Goshu E, Lévy E, et al. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet. 2001;10(14):1465–73.

    Article  CAS  PubMed  Google Scholar 

  82. Tolson KP, Gemelli T, Gautron L, Elmquist JK, Zinn AR, Kublaoui BM. Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression. J Neurosci. 2010;30(10):3803–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kublaoui BM, Holder JL Jr, Gemelli T, Zinn AR. Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons. Mol Endocrinol. 2006;20(10):2483–92.

    Article  CAS  PubMed  Google Scholar 

  84. Holder JL, Butte NF, Zinn AR. Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet. 2000;9(1):101–8.

    Article  CAS  PubMed  Google Scholar 

  85. Izumi K, Housam R, Kapadia C, Stallings VA, Medne L, Shaikh TH, et al. Endocrine phenotype of 6q16.1-q21 deletion involving SIM1 and Prader-Willi syndrome-like features. Am J Med Genet A. 2013;161A(12):3137–43.

    Article  PubMed  CAS  Google Scholar 

  86. Bonnefond A, Raimondo A, Stutzmann F, Ghoussaini M, Ramachandrappa S, Bersten DC, et al. Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features. J Clin Invest. 2013;123(7):3037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Montagne L, Raimondo A, Delobel B, Duban-Bedu B, Noblet FS, Dechaume A, et al. Identification of two novel loss-of-function SIM1 mutations in two overweight children with developmental delay. Obesity. 2014;22(12):2621–4.

    CAS  PubMed  Google Scholar 

  88. Ramachandrappa S, Raimondo A, Cali AM, Keogh JM, Henning E, Saeed S, et al. Rare variants in single-minded 1 (SIM1) are associated with severe obesity. J Clin Invest. 2013;123(7):3042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gray J, Yeo GS, Cox JJ, Morton J, Adlam A-LR, Keogh JM, et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes. 2006;55(12):3366–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med. 2008;359(9):918–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shinawi M, Sahoo T, Maranda B, Skinner SA, Skinner C, Chinault C, et al. 11p14.1 microdeletions associated with ADHD, autism, developmental delay, and obesity. Am J Med Genet A. 2011;155A(6):1272–80.

    Article  PubMed  CAS  Google Scholar 

  92. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci. 2003;6(7):736–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yeo GS, Hung C-CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci. 2004;7(11):1187–9.

    Article  CAS  PubMed  Google Scholar 

  94. Gray J, Yeo G, Hung C, Keogh J, Clayton P, Banerjee K, et al. Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity. Int J Obes. 2007;31(2):359–64.

    Article  CAS  Google Scholar 

  95. Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet. 1996;13:485–8.

    Article  CAS  PubMed  Google Scholar 

  96. Doche ME, Bochukova EG, Su H-W, Pearce LR, Keogh JM, Henning E, et al. Human SH2B1 mutations are associated with maladaptive behaviors and obesity. J Clin Invest. 2012;122(12):4732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Li Z, Zhou Y, Carter-Su C, Myers MG Jr, Rui L. SH2B1 enhances leptin signaling by both Janus kinase 2 Tyr813 phosphorylation-dependent and-independent mechanisms. Mol Endocrinol. 2007;21(9):2270–81.

    Article  CAS  PubMed  Google Scholar 

  98. Rui L, Carter-Su C. Identification of SH2-Bβ as a potent cytoplasmic activator of the tyrosine kinase Janus kinase 2. Proc Natl Acad Sci. 1999;96(13):7172–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rui L, Gunter DR, Herrington J, Carter-Su C. Differential binding to and regulation of JAK2 by the SH2 domain and N-terminal region of SH2-Bβ. Mol Cell Biol. 2000;20(9):3168–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pearce LR, Joe R, Doche ME, Su H-W, Keogh JM, Henning E, et al. Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1. Endocrinology. 2014;155(9):3219–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Bachmann-Gagescu R, Mefford HC, Cowan C, Glew GM, Hing AV, Wallace S, et al. Recurrent 200-kb deletions of 16p11. 2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med. 2010;12(10):641–7.

    Article  PubMed  Google Scholar 

  102. Walters R, Jacquemont S, Valsesia A, De Smith A, Martinet D, Andersson J, et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11. 2. Nature. 2010;463(7281):671–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Pearce LR, Atanassova N, Banton MC, Bottomley B, van der Klaauw AA, Revelli J-P, et al. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. Cell. 2013;155(4):765–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Revelli JP, Smith D, Allen J, Jeter-Jones S, Shadoan MK, Desai U, et al. Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2. Obesity. 2011;19(5):1010–8.

    Article  CAS  PubMed  Google Scholar 

  105. Huvenne H, Dubern B, Clement K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obes Facts. 2016;9(3):1–73.

    Article  CAS  Google Scholar 

  106. Choquet H, Meyre D. Genomic insights into early-onset obesity. Genome Med. 2010;2(6):36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Tarnanas I, Tsolaki A, Wiederhold M, Wiederhold B, Tsolaki M. Five-year biomarker progression variability for Alzheimer’s disease dementia prediction: can a complex instrumental activities of daily living marker fill in the gaps? Alzheimers Dement (Amst). 2015;1(4):521–32.

    Google Scholar 

  108. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Phan-Hug F, Beckmann JS, Jacquemont S. Genetic testing in patients with obesity. Best Pract Res Clin Endocrinol Metab. 2012;26(2):133–43.

    Article  CAS  PubMed  Google Scholar 

  110. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341(12):879–84.

    Article  CAS  PubMed  Google Scholar 

  112. Farooqi IS, Bullmore E, Keogh J, Gillard J, O’Rahilly S, Fletcher PC. Leptin regulates striatal regions and human eating behavior. Science. 2007;317(43):1355.

    Article  CAS  PubMed  Google Scholar 

  113. Frank S, Heni M, Moss A, von Schnurbein J, Farooqi S, Häring H-U, et al. Long-term stabilization effects of leptin on brain functions in a leptin-deficient patient. PLoS One. 2013;8(6):e693.

    Article  CAS  Google Scholar 

  114. Reinehr T, Hebebrand J, Friedel S, Toschke AM, Brumm H, Biebermann H, et al. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity (Silver Spring). 2009;17(2):382–9.

    Article  CAS  Google Scholar 

  115. Santoro N, Perrone L, Cirillo G, Raimondo P, Amato A, Coppola F, et al. Weight loss in obese children carrying the proopiomelanocortin R236G variant. J Endocrinol Investig. 2006;29(3):226–30.

    Article  CAS  Google Scholar 

  116. Kuhnen P, Clement K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, et al. Proopiomelanocortin deficiency treated with a Melanocortin-4 receptor agonist. N Engl J Med. 2016;375(3):240–6.

    Article  PubMed  CAS  Google Scholar 

  117. Aslan IR, Ranadive SA, Ersoy BA, Rogers SJ, Lustig RH, Vaisse C. Bariatric surgery in a patient with complete MC4R deficiency. Int J Obes. 2011;35(3):457–61.

    Article  CAS  Google Scholar 

  118. Valette M, Poitou C, Le Beyec J, Bouillot JL, Clement K, Czernichow S. Melanocortin-4 receptor mutations and polymorphisms do not affect weight loss after bariatric surgery. PLoS One. 2012;7(11):e48221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Meyre D, Froguel P, Horber FF, Kral JG, Valette M, et al. Melanocortin-4 receptor mutations and polymorphisms do not affect weight loss after bariatric surgery. PLoS One. 2012;7(11):E48221. PLoS One. 2014;9(3):e93324

    Article  CAS  Google Scholar 

  120. Moore BS, Mirshahi UL, Yost EA, Stepanchick AN, Bedrin MD, Styer AM, et al. Long-term weight-loss in gastric bypass patients carrying melanocortin 4 receptor variants. PLoS One. 2014;9(4):e93629.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Bonnefond A, Keller R, Meyre D, Stutzmann F, Thuillier D, Stefanov DG, et al. Eating behavior, low-frequency functional mutations in the Melanocortin-4 receptor (MC4R) gene, and outcomes of bariatric operations: a 6-year prospective study. Diabetes Care. 2016;39(8):1384–92.

    Article  CAS  PubMed  Google Scholar 

  122. Ho AL, Sussman ES, Pendharkar AV, Azagury DE, Bohon C, Halpern CH. Deep brain stimulation for obesity: rationale and approach to trial design. Neurosurg Focus. 2015;38(6):E8.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada

    Marie Pigeyre MD, PhD & David Meyre PhD

  2. Department of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada

    Marie Pigeyre MD, PhD & David Meyre PhD

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  1. Marie Pigeyre MD, PhD
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Correspondence to David Meyre PhD .

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  1. Duke University School of Medicine , Durham, North Carolina, USA

    Michael S. Freemark

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Pigeyre, M., Meyre, D. (2018). Monogenic Obesity. In: Freemark, M. (eds) Pediatric Obesity. Contemporary Endocrinology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-68192-4_8

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