Genetic Evaluation of a Hereditary Familial Severe Obesity Due to Naturally Occurring Mutation in the Leptin Receptor and Structure Homology Modelling of the Mutated Molecule

Document Type : Original Article(s)

Authors

1 Assistant Professor, Departmen of Giology, School of Scisnse, The University of Malayer, Malayer, Iran

2 Assistant Professor, Departmen of Giology, School of Scisnse, The University of Isfahan, Isfahan, Iran

Abstract

Introduction: Obesity, a growing universal problem, is a disorder/illness related to several factors. These factors includ environmental, metabolic and genetic factors. Genetic studies have been undertaken for several different causative mutations involving obesity genes on different chromosomes and few mutations have been reported in that regard. Leptin is one of the most important adipose derived hormones with important role in regulating body weight through the inhibition of food intake and stimulation of energy expenditure. This hormone binds to leptin receptor that is present in surface of a number of cells especially to the ventromedial nucleus of the hypothalamus, known as the appetite centre, and it can activate intracellular signalling domains. A very small group of humans possess homozygous mutations for the leptin/leptin receptor genes which lead to a constant desire for food, resulting in severe obesity.Methods: Here we introduce a hereditary familial mutation in leptin receptor gene of two young sisters from a Kurdish-Turkish family who were suffering from severe obesity. Blood samples were taken from all member of the family and DNA was extracted from leukocytes. Sequencing was performed for suspected genes involving in severe obesity. Canonical structures Swiss homology modelling of these molecules was prepared.Finding: Data analysis showed that two sisters were homozygous for two different missense mutations in the leptin receptor. Their parents were heterozygous for these mutations.Conclusion: The data suggests that these mutations have impaired the leptin signalling and therefore have caused severe obesity in these two sisters.

Keywords

References

  1. Rosenbaum M, Leibel RL. The role of leptin in human physiology. N Engl J Med 1999; 341(12): 913-5.
  2. Qiu J, Ogus S, Mounzih K, Ewart-Toland A, Chehab FF. Leptin-deficient mice backcrossed to the BALB/cJ genetic background have reduced adiposity, enhanced fertility, normal body temperature, and severe diabetes. Endocrinology 2001; 142(8): 3421-5.
  3. Cohen SL, Halaas JL, Friedman JM, Chait BT, Bennett L, Chang D, et al. Human leptin characterization. Nature 1996; 382(6592): 589.
  4. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83(7): 1263-71.
  5. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996; 84(3): 491-5.
  6. Tartaglia LA. The leptin receptor. J Biol Chem 1997; 272(10): 6093-6.
  7. Matarese G, La Cava A, Sanna V, Lord GM, Lechler RI, Fontana S, et al. Balancing susceptibility to infection and autoimmunity: a role for leptin? Trends Immunol 2002; 23(4): 182-7.
  8. Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 1996; 387(2-3): 113-6.
  9. Hegyi K, Fülöp K, Kovacs K, Toth S, Falus A. Leptin-induced signal transduction pathways. Cell Biol Int 2004; 28(3): 159-69.
  10. Winick JD, Stoffel M, Friedman JM. Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1. Genomics 1996; 36(1): 221-2.
  11. Laschober GT, Brunauer R, Jamnig A, Fehrer C, Greiderer B, Lepperdinger G. Leptin recep-tor/CD295 is upregulated on primary human mesenchymal stem cells of advancing biological age and distinctly marks the subpopulation of dying cells. Exp Gerontol 2009; 44(1-2): 57-62.
  12. Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, et al. Transient increase in obese gene expression after food intake or insulin administration. Nature 1995; 377(6549): 527-9.
  13. Peelman F, Couturier C, Dam J, Zabeau L, Tavernier J, Jockers R. Techniques: new phar-macological perspectives for the leptin receptor. Trends Pharmacol Sci 2006; 27(4): 218-25.
  14. Kimber W, Peelman F, Prieur X, Wangensteen T, O'Rahilly S, Tavernier J, et al. Functional characterization of naturally occurring pathogenic mutations in the human leptin receptor. Endocrinology 2008; 149(12): 6043-52.
  15. Peelman F, Iserentant H, De Smet AS, Van-dekerckhove J, Zabeau L, Tavernier J. Mapping of binding site III in the leptin receptor and modeling of a hexameric leptin.leptin receptor complex. J Biol Chem 2006; 281(22): 15496-504.
  16. La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol 2004; 4(5): 371-9.
  17. Chang Bioscience Inc. Primo Sequencing 3.4: Sequencing Primer Design. Available from: URL: http://www.changbioscience.com/primo/primoseq.html
  18. Biology Department, Davidson College. Human Leptin and Leptin Receptor Prtein Sequences. Available from: URL:
  19. http://www.bio.davidson.edu/courses/genomics/chime/leptinseq.html
  20. Bioinformatics Organization. Reverse comple-ment. Available from: URL:
  21. http://www.bioinformatics.org/sms/rev_comp.html
  22. Swiss Institute of Bioinformatics. SWISS-MODEL. Available from: URL: http://swissmodel.expasy.org//SWISS-MODEL.html
  23. Schwede T, Kopp J, Guex N, Peitsch MC. SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res 2003; 31(13): 3381-5.
  24. Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 1997; 18(15): 2714-23.
  25. Peitsch MC. Protein modeling by e-mail. Nature Biotechnology 1995; 13: 658-60.
  26. University of Massachusetts Amherst. Free softwares. Available from: URL: http://www.umass.edu/microbio.rasmol/
  27. Farooqi IS, O'Rahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr 2009; 89(3): 980S-4S.
  28. 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.
  29. Comuzzie AG, Allison DB. The search for hu-man obesity genes. Science 1998; 280(5368): 1374-7.
  30. Sweeney G. Leptin signalling. Cell Signal 2002; 14(8): 655-63.
  31. Sanchez-Margalet V, Martin-Romero C. Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway. Cell Immunol 2001; 211(1): 30-6.
  32. Bjorbaek C, Buchholz RM, Davis SM, Bates SH, Pierroz DD, Gu H, et al. Divergent roles of SHP-2 in ERK activation by leptin receptors. J Biol Chem 2001; 276(7): 4747-55.
  33. Banks AS, Davis SM, Bates SH, Myers MG, Jr. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000; 275(19): 14563-72.
  34. van Den Brink EN, Turenhout EA, Davies J, Bovenschen N, Fijnvandraat K, Ouwehand WH, et al. Human antibodies with specificity for the C2 domain of factor VIII are derived from VH1 germline genes. Blood 2000; 95(2): 558-63.
  35. De Rosa V, Procaccini C, Calì G, Pirozzi G, Fontana S, Zappacosta S, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 2007; 26(2): 241-55.
  36. Zabeau L, Defeau D, Iserentant H, Van-dekerckhove J, Peelman F, Tavernier J. Leptin receptor activation depends on critical cysteine residues in its fibronectin type III subdomains. J Biol Chem 2005; 280(24): 22632-40.
  37. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, et al. Clinical and molecular genetic spectrum of congenital defi-ciency of the leptin receptor. N Engl J Med 2007; 356(3): 237-47.
  38. Iserentant H, Peelman F, Defeau D, Van-dekerckhove J, Zabeau L, Tavernier J. Mapping of the interface between leptin and the leptin receptor CRH2 domain. J Cell Sci 2005; 118(Pt 11): 2519-27.
  39. Zabeau L, Defeau D, Van der HJ, Iserentant H, Vandekerckhove J, Tavernier J. Functional analysis of leptin receptor activation using a Janus kinase/signal transducer and activator of transcription complementation assay. Mol Endocrinol 2004; 18(1): 150-61.
Journal of Isfahan Medical School
Volume 28, Issue 121 - Serial Number 121
November and December 2011
Pages 1606-1616

Files

History

  • Receive Date: 27 February 2011
  • Revise Date: 07 May 2024
  • Accept Date: 06 April 2022

Share

How to cite

Statistics