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Monogenic obesity – current status of molecular genetic research and clinical importance


Authors: Irena Aldhoon-Hainerová 1,2;  Josef Včelák 1;  Hana Zamrazilová 1
Authors‘ workplace: Endokrinologický ústav, Praha 1;  Klinika dětí a dorostu 3. LF UK a FNKV, Praha 2
Published in: Čas. Lék. čes. 2014; 153: 200-206
Category: Review Articles

Overview

Obesity and its comorbidities represent one of the major health problems worldwide. A positive energy balance due to inappropriate life-style changes plays a key role in the current obesity epidemic. The influence of genetic factors is also significant – several studies concluded that genes contribute to the development of obesity by 40–70%. Genetic variability predisposes an individual to tendency or resistance to increase body weight in obesogenic environment. Polygenic type of inheritance is responsible in most of obese individuals. However, an intensive research of the past 20 years has led to an identification of several genes causing monogenic forms of obesity. To date, several monogenic genes (leptin, leptin receptor, prohormon convertase 1, proopiomelanocortin, melanocortin 4 receptor, single-minded homolog 1, brain-derived neurotrophic factor, neurotrophic tyrosine kinase receptor type 2) that are either involved in the neuronal differentiation of the paraventricular nucleus or in the leptin-melanocortin pathway are known to cause obesity. Mutation carriers apart from severe early onset obesity manifest with additional phenotypic characteristics as adrenal insufficiency, impaired immunity and impaired fertility. This review provides an overview of molecular-genetic and clinical research in the field of monogenic obesities including therapeutical approaches.

Keywords:
monogenic obesity – energy balance regulation – leptin – leptin receptor – proopiomelanocortin – melanocortin receptor – prohormon convertase – single-minded homolog 1 – brain-derived neurotrophic factor – neurotrophic tyrosine kinase receptor type 2


Sources

1. Ingalls AM, et al. Obese, a new mutation in the house mouse. Obes Res 1996; 4: 101.

2. Ingalls AM, et al. Obese, a new mutation in the house mouse. J Hered 1950; 41: 317–318.

3. Houseknecht KL, et al. The biology of leptin: a review. J Anim Sci 1998; 76: 1405–1420.

4. Zhang Y, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425–432.

5. Chua SC, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996; 271: 994–996.

6. Saeed S, et al. High prevalence of leptin and melanocortin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families. Mol Genet Metab 2012; 106(1): 121–126.

7. Montague CT, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903–908.

8. Echwald SM, et al. Identification of two novel missense mutations in the human OB gene. Int J Obes Relat Metab Disord 1997; 21: 321–326.

9. Karvonen MK, et al. Identification of new sequence variants in the leptin gene. J Clin Endocrinol Metab 1998; 83(9): 3239–3242.

10. Saeed S, et al. Changes in levels of peripheral hormones controlling appetite are inconsistent with hyperphagia in leptin-deficient subjects. Endocrine 2014; 45(3): 401–408.

11. Oksanen L, et al. Novel polymorphism of the human ob gene promoter in lean and morbidly obese subjects. Int J Obes Relat Metab Disord 1997; 21: 489–494.

12. Farooqi IS, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341(12): 879–884.

13. Farooqi IS, 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): 1093–1103.

14. Galgani JE, et al. Leptin replacement prevents weight loss-induced metabolic adaptation in congenital leptin-deficient patients. J Clin Endocrinol Metab 2010; 95: 851–855.

15. Andreev VP, et al. Deconvolution of insulin secretion, insulin hepatic extraction post-hepatic delivery rates and sensitivity during 24-hour standardized meals: time course of glucose homeostasis in leptin replacement treatment. Horm Metab Res 2009; 41: 142–151.

16. Frank S, et al. Long-term stabilization effects of leptin on brain functions in a leptin-deficient patient. PLoS One 2013; 14: e65893.

17. von Schnurbein J, et al. Rapid improvement of hepatic steatosis after initiation of leptin substitution in a leptin-deficient girl. Horm Res Paediatr 2013; 79(5): 310–317.

18. Mazen I, et al. 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): 461–464.

19. Andiran N, et al. 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): 1043–1045.

20. Clement K, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398–401.

21. Masuo K, et al. Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population. Hypertens Res 2008; 31: 1093–1100.

22. Heo M, et al. Pooling analysis of genetic data: the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity. Genetics 2001; 159(3): 1163–1178.

23. Le Beyec J, 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.

24. Zhou A, et al. The prohormone convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a strict temporal order during proopiomelanocortin biosynthesis processing. J Biol Chem 1993; 268(3): 1763–1769.

25. Jackson RS, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1. Na. Genet 1997; 16: 303–306.

26. Jackson RS, et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 2003; 112: 1550–1560.

27. Farooqi IS, et al. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab 2007; 92: 3369–3373.

28. Seidah NG. The proprotein convertases, 20 years later. Methods Mol Biol 2011; 768: 23–57.

29. Martín MG, et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology 2013; 145(1): 138–148.

30. Benzinou M, et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet 2008; 40: 943–945.

31. O’Donohue TL, Dorsa DM. The opiomelanotropinergic neuronal and endocrine system. Peptides 1982; 3(3): 353–395.

32. Whitfeld PL, et al. The human pro-opiomelanocortin gene. DNA 1982; 143(1): 133–143.

33. Clément K, et al. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. Clin Endocrinol Metab 2008; 93(12): 4955–4962.

34. Krude H, et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 2003; 88(10): 4633–4640.

35. Krude H, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19(2): 155–157.

36. Krude H, Gruters A. Implications of proopiomelanocortin (POMC) mutations in humans: the POMC deficiency syndrome. Trends Endocrinol Metab 2000; 11(1): 15–22.

37. Aldhoon-Hainerová I, Lebl J. Treatment options for children with monogenic forms of obesity. World Rev Nutr Diet 2013; 106: 105–112.

38. Santoro N, et al. Weight loss in obese children carrying the proopiomelanocortin R236G variant. J Endocrinol Invest 2006; 29: 226–230.

39. Gantz I, et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem 1993; 15(20): 15174–15179.

40. Hainerová I, et al. Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis. J Clin Endocrinol Metab 2007; 92: 3689–3696.

41. Martinelli CE, et al. Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion. J Clin Endocrinol Metab 2011; 96(1): E181–E188.

42. Hinney A, et al. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J Clin Endocrinol Metab 2006; 91: 1761–1769.

43. Roubert P, et al. Novel pharmacological MC4R agonists can efficiently activate mutated MC4R from obese patient with impaired endogenous agonist response. J Endocrinol 2010; 207: 177–1783.

44. René P, et al. Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity. J Pharmacol Exp Ther 2010; 335: 520–532.

45. Reinehr T, et al. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity (Silver Spring) 2009; 17: 382–389.

46. Danielsson P, et al. Impact sibutramine therapy in children with hypothalamic obesity or obesity with aggravating syndromes. J Clin Endocrinol Metab 2007; 92: 4101–4106.

47. Aldhoon Hainerová I, et al. Hypogonadotropic hypogonadism in a homozygous MC4R mutation carrier and the effect of sibutramine treatment on body weight and obesity-related health risks. Obes Facts 2011; 4(4): 324–328.

48. Potoczna N, et al. Gene variants and binge eating as predictors of comorbidity and outcome of treatment in severe obesity. J Gastrointest Surg 2004; 8: 971–981.

49. Aslan IR, et al. Bariatric surgery in a patient with complete MC4R deficiency. Int J Obes (Lond) 2011; 35: 457–461.

50. Aslan IR, et al. Weight loss after Roux-en-Y gastric bypass in obese patients heterozygous for MC4R mutations. Obes Surg 2011; 21: 930–934.

51. Hatoum IJ, et al. Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery. J Clin Endocrinol Metab 2012; 97(6): E1023–E1031.

52. Michaud JL, et al. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet 2001; 10: 1465–1473.

53. Holder JL, et al. Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 2000; 9: 101–108.

54. Hung CC, et al. Studies of the SIM1 gene in relation to humanobesity and obesity-related traits. Int J Obes (Lond) 2007; 31(3): 429–434.

55. Zegers D, et al. Mutation screen of the SIM1 gene in pediatric patients with early-onset obesity. Int J Obes (Lond) 2013; Epub ahead of print.

56. Ramachandrappa S, et al. Rare variants in single-minded 1 (SIM1) are associated with severe obesity. J Clin Invest 2013; 123(7): 3042–3050.

57. Xu Y, et al. Glutamate mediates the function of melanocortin receptor 4 on Sim1 neurons in body weight regulation. Cell Metab 2013; 18(6): 860–870.

58. Xu B, et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci 2003; 6: 736–742.

59. Yeo GS, et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 2004; 7: 1187–1189.

60. Gray J, 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): 3366–3371.

61. Han JC, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 2008; 359(9): 918–927.

62. Gray J, et al. Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity. Int J Obes (Lond) 2007; 31(2): 359–364.

63. Lee YS, et al. The role of melanocortin 3 receptor gene in childhood obesity. Diabetes 2007; 56(10): 2622–2630.

64. Zegers D, et al. Prevalence of rare MC3R variants in obese cases and lean controls. Endocrine 2013; 44(2): 386–390.

65. Feng N, et al. Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity. Diabetes 2005; 54(9): 2663–2667.

66. Santoro N, et al. Effect of the melanocortin-3 receptor C17A and G241A variants on weight loss in childhood obesity. Am J Clin Nutr 2007; 85(4): 950–953.

67. Santos JL, et al. Consortium Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets. PLoS One 2011; 6(6): e19934.

68. Lee YS. Melanocortin 3 receptor gene and melanocortin 4 receptor gene mutations: the Asian Perspective. Diabetes Metab Res Rev 2012; 28: 26–31.

69. Bonnefond A, et al. Highly sensitive diagnosis of 43 monogenic forms of diabetes or obesity through one-step PCR-based enrichment in combination with next-generation sequencing. Diabetes Care 2014; 37(2): 460–467.

70. Bochukova EG, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010; 463: 666–670.

71. Doche ME, et al. Human SH2B1 mutations are associated with maladaptive behaviors and obesity. J Clin Invest 2012; 122(12): 4732–4736.

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