Genetic Obesity Syndromes

Chapter

Abstract

A number of genetic obesity syndromes have been identified by sequencing candidate genes in patients with severe obesity. Many of the initial findings emerged from studying families who displayed a classical Mendelian pattern of inheritance; however, with more comprehensive genome wide approaches, increasingly more complex models of inheritance are likely to emerge. The functional and physiological characterization of the human obesity syndromes has provided information that has diagnostic value (Fig. 2.1), has led to specific treatments in some patients and continues to provide insights into the mechanisms involved in the regulation of body weight in humans.

Keywords

Obesity Tyrosine Corticosteroid Serine Hypothyroidism 

References

  1. 1.
    Goldstone AP (2004) Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab 15:12–20CrossRefPubMedGoogle Scholar
  2. 2.
    Carrel AL, Allen DB (2001) Prader-Willi syndrome: how does growth hormone affect body composition and physical function? J Pediatr Endocrinol Metab 14(Suppl 6):1445–1451PubMedGoogle Scholar
  3. 3.
    Haqq AM, Farooqi IS, O’Rahilly S et al (2003) Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome. J Clin Endocrinol Metab 88:174–178CrossRefPubMedGoogle Scholar
  4. 4.
    de Smith AJ, Purmann C, Walters RG et al (2009) A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. Hum Mol Genet 18:3257–3265CrossRefPubMedGoogle Scholar
  5. 5.
    Sahoo T, del Gaudio D, German JR et al (2008) Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet 40:719–721CrossRefPubMedGoogle Scholar
  6. 6.
    Weinstein LS, Chen M, Liu J (2002) Gs(alpha) mutations and imprinting defects in human disease. Ann N Y Acad Sci 968:173–197CrossRefPubMedGoogle Scholar
  7. 7.
    Ansley SJ, Badano JL, Blacque OE et al (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425:628–633CrossRefPubMedGoogle Scholar
  8. 8.
    Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC (2009) Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet 18:1323–1331CrossRefPubMedGoogle Scholar
  9. 9.
    Yeo GS, Connie Hung CC, Rochford J et al (2004) A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7:1187–1189CrossRefPubMedGoogle Scholar
  10. 10.
    Gray J, Yeo GS, Cox JJ et al (2006) Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55:3366–3371CrossRefPubMedGoogle Scholar
  11. 11.
    Han JC, Liu QR, Jones M et al (2008) Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 359:918–927CrossRefPubMedGoogle Scholar
  12. 12.
    Holder JL Jr, Butte NF, Zinn AR (2000) Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 9:101–108CrossRefPubMedGoogle Scholar
  13. 13.
    Kublaoui BM, Gemelli T, Tolson KP, Wang Y, Zinn AR (2008) Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. Mol Endocrinol 22:1723–1734CrossRefPubMedGoogle Scholar
  14. 14.
    Huszar D, Lynch CA, Fairchild-Huntress V et al (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141CrossRefPubMedGoogle Scholar
  15. 15.
    Farooqi IS, Wangensteen T, Collins S et al (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356:237–247CrossRefPubMedGoogle Scholar
  16. 16.
    Farooqi IS, Matarese G, Lord GM et al (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110:1093–1103PubMedGoogle Scholar
  17. 17.
    Farooqi IS, Jebb SA, Langmack G et al (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884CrossRefPubMedGoogle Scholar
  18. 18.
    Farooqi IS, Bullmore E, Keogh J, Gillard J, O’Rahilly S, Fletcher PC (2007) Leptin regulates striatal regions and human eating behavior. Science 317:1355CrossRefPubMedGoogle Scholar
  19. 19.
    Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J (2008) Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. J Clin Invest 118:2583–2591PubMedGoogle Scholar
  20. 20.
    Krude H, Biebermann H, Schnabel D et al (2003) Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 88:4633–4640CrossRefPubMedGoogle Scholar
  21. 21.
    Challis BG, Pritchard LE, Creemers JW et al (2002) 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 11:1997–2004CrossRefPubMedGoogle Scholar
  22. 22.
    Lee YS, Challis BG, Thompson DA et al (2006) A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab 3:135–140CrossRefPubMedGoogle Scholar
  23. 23.
    Seidah NG (2011) The proprotein convertases, 20 years later. Methods Mol Biol 768:23–57CrossRefPubMedGoogle Scholar
  24. 24.
    Jackson RS, Creemers JW, Ohagi S et al (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene [see comments]. Nat Genet 16:303–306CrossRefPubMedGoogle Scholar
  25. 25.
    Jackson RS, Creemers JW, Farooqi IS et al (2003) Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 112:1550–1560PubMedGoogle Scholar
  26. 26.
    Stutzmann F, Tan K, Vatin V et al (2008) Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 57:2511–2518CrossRefPubMedGoogle Scholar
  27. 27.
    Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348:1085–1095CrossRefPubMedGoogle Scholar
  28. 28.
    Martinelli CE, Keogh JM, Greenfield JR et al (2011) 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 96:E181–E188CrossRefPubMedGoogle Scholar
  29. 29.
    Greenfield JR, Miller JW, Keogh JM et al (2009) Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med 360:44–52CrossRefPubMedGoogle Scholar
  30. 30.
    Hatoum IJ, Stylopoulos N, Vanhoose AM et al (2012) Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery. J Clin Endocrinol Metab 97:E1023–E1031CrossRefPubMedGoogle Scholar
  31. 31.
    Wheeler E, Huang N, Bochukova EG et al (2013) Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet 45:513–517CrossRefPubMedGoogle Scholar
  32. 32.
    Bochukova EG, Huang N, Keogh J et al (2010) Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463:666–670CrossRefPubMedGoogle Scholar
  33. 33.
    Doche ME, Bochukova EG, Su HW et al (2012) Human SH2B1 mutations are associated with maladaptive behaviors and obesity. J Clin Invest 122:4732–4736CrossRefPubMedGoogle Scholar
  34. 34.
    Dietz WH, Robinson TN (2005) Clinical practice. Overweight children and adolescents. N Engl J Med 352:2100–2109CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Metabolic Diseases UnitWellcome Trust-MRC Institute of Metabolic ScienceCambridgeUK

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