Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Molecular screening of the proopiomelanocortin (POMC ) gene in Italian obese children: report of three new mutations

International Journal of Obesity volume 25, pages 61–67 (2001)Cite this article

Abstract

BACKGROUND: Although linkage studies strongly suggest that proopiomelanocortin (POMC) alterations could play a role in the genetic predisposition to obesity, systematic POMC mutational analysis did not completely confirm this hypothesis.

OBJECTIVES: To verify the presence of mutations of the POMC coding region in Italian children with very early onset obesity.

SUBJECTS AND METHODS: Eighty seven unrelated Italian obese children and adolescents were studied. Mean age at obesity onset was 4.7±2.5 y. The POMC gene coding region was screened using single-strand conformation polymorphism (SSCP) analysis. Bi-directional automatic sequencing of PCR products was performed for all individuals who showed an aberrant SSCP pattern.

RESULTS: Three new mutations have been identified in the heterozygous state in three patients: (a) G3834C, resulting in the substitution of Ser with Thr at codon 7 within the POMC signal peptide; (b) C3840T, resulting in the substitution of Ser with Leu at codon 9 of the pre-proopiomelanocortin signal peptide; and (c) C7406G, producing the substitution of Arg with Gly at codon 236 within the β-endorphin peptide. A polymorphism consisting of a 9 bp insertion, AGC AGC CGC, between position 6997 and 6998 has been found at the heterozygous state in nine patients. They showed leptin levels adjusted for BMI, gender and pubertal stage significantly higher than obese subjects homozyous for the POMC wild-type allele.

CONCLUSIONS: Mutations in codons 7 and 9 of the signal peptide may alter the translocation of the pre-proopiomelanocortin into the endoplasmic reticulum and, therefore, can be implicated in obesity. Although further studies are required, the polymorphism between position 6997 and 6998 may represent one of the genetic variations that explain the linkage between obesity and POMC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Stunkard AJ, Sorensen TIA, Hanis C, Teasdale TW, Chakraborty R, Schull WJ, Schulsinger F . An adoption study of human obesity New Engl J Med 1986 314: 193–198.

    Article  CAS  PubMed  Google Scholar 

  2. Stunkard AJ, Harris JR, Pedersen NL, McClearen GE . The body mass index of twins who have been reared apart New Engl J Med 1990 322: 1483–1487.

    Article  CAS  PubMed  Google Scholar 

  3. Clement K . Leptin and the genetics of obesity Acta Paediatr 1999 88: 51–57.

    Article  CAS  Google Scholar 

  4. Takahashi H, Teranishi Y, Nakanishi S, Numa S . Isolation and structural organization of the human corticotropin-β-lipotropin precursor gene FEBS Lett 1981 135: 97–101.

    Article  CAS  PubMed  Google Scholar 

  5. Takahashi H, Hakamata Y, Watanabe Y, Kikuno R, Miyata T, Numa S . Complete nucleotide sequence of the human corticotropin-β-lipotropin precursor gene Nucleic Acids Res 1983 11: 6847–6858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Swartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG . Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus Diabetes 1997 46: 2119–2123.

    Article  Google Scholar 

  7. Boston BA, Balydon KM, Varnerin J, Cone RD . Independent and additive effects of central POMC and Leptin Pathways on murine obesity Science 1997 278: 1641–1644.

    Article  CAS  PubMed  Google Scholar 

  8. Mizuno TM, Kleopoulos SP, Bergen HT, Roberts JL, Priest CA, Mobbs CV . Hypotlamic pro-opiomelanocortin mRNA is reduced by fasting in ob/ob and db/db mice, but is stimulated by leptin Diabetes 1998 47: 294–297.

    Article  CAS  PubMed  Google Scholar 

  9. Yaswen L, Diehl N, Brennan MB, Hochgeschwender U . Obesity in the mouse of pro-opiomelanocortin deficiency responds to peripheral melanocortin Nature Med 1999 5: 1066–1070.

    Article  CAS  PubMed  Google Scholar 

  10. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, Maccluer JW, Blangero J . A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2 Nature Genet 1997 15: 273–276.

    Article  CAS  PubMed  Google Scholar 

  11. Hager J, Dina C, Francke S, Dubois S, Houari M, Vatin V, Vaillant E, Lorentz N, Basdevant A, Clement K, Guy-Grand B, Froguel P . A genome-wide scan for human obesity genes reveals a major susceptility locus on chromosome 10 Nature Genet 1998 20: 304–308.

    Article  CAS  PubMed  Google Scholar 

  12. Krude H, Biebermann H, Luck W, Rudiger H, Brabrant G, Gruters A . Severe early onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans Nature Genet 1998 19: 155–157.

    Article  CAS  PubMed  Google Scholar 

  13. Hinney A, Becker I, Heibult O, Nottebom K, Schmidt A, Ziegler A, Mayer H, Siegfried W, Blum WF, Remschmidt H, Hebebrand J . Systematic mutation screening of the proopiomelanocortin gene: identification of several genetic variants including three different insertions, one nonsense and two missense point mutations in probands of different weight extremes J Clin Endocrinol Metab 1998 83: 3737–3741.

    Article  CAS  PubMed  Google Scholar 

  14. Echwald SM, Sorensen TIA, Andersen T, Tybjaerg-Hansen A, Clausen JO, Pedersen O . Mutational analysis of the proopiomelanocortin gene in caucasians with early onset obesity Int J Obes Relat Metab Disord 1999 23: 293–298.

    Article  CAS  PubMed  Google Scholar 

  15. Korkeila M, Kaprio J, Rissanen A, Koskenvuo M . Effects of gender and age on the heritability of body mass index Int J Obes 1991 15: 647–654.

    CAS  PubMed  Google Scholar 

  16. Herskind AM, McGue M, Sorensen TIA, Harvald B . Sex and age specific assessment of genetic and environmental influences on body mass index in twins Int J Obes Relat Metab Disord 1996 20: 106–113.

    CAS  PubMed  Google Scholar 

  17. Rolland-Cachera MF, Cole TJ, Sempé M, Tichet J, Rossignol C, Charraud A . Variation of the Wt/Ht2 index from birth to 87 y Eur J Clin Nutr 1991 45: 13–21.

    CAS  PubMed  Google Scholar 

  18. Blum WF, Englaro P, Hanitsch S, Juul A, Hertel NT, Muller J, Skakkebaek NE, Heiman ML, Birkett M, Attanasio AM, Kiess W, Rascher W . Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone J Clin Endocrinol Metab 1997 82: 2904–2910.

    CAS  PubMed  Google Scholar 

  19. Hixson JE, Almasy L, Cole S, Mitchell BD, Mahaney MC, Stern MP, MacCluer JW, Blangero J, Comuzzie AG . Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC J Clin Endocrinol Metab 1999 84: 3187–3191.

    CAS  PubMed  Google Scholar 

  20. von Heijne G . The signal peptide J Membr Biol 1990 115:: 195–201.

    Article  Google Scholar 

  21. von Heijne G . Sec-independent protein insertion into the inner E. coli membrane. A phenomenon in search of an explanation FEBS Lett 1994 346: 69–72.

    Article  CAS  PubMed  Google Scholar 

  22. Andersson H, von Heijne G . Positively charged residues influence the degree of SecA dependence in protein translocation across the E. coli inner membrane FEBS Lett 1994 347: 169–172.

    Article  CAS  PubMed  Google Scholar 

  23. Gafvelin G, Sakaguchi M, Andersson H, von Heijne G . Topological rules for membrane protein assembly in eukaryotic cells J Biol Chem 1997 272: 6119–6127.

    Article  CAS  PubMed  Google Scholar 

  24. Siggaard C, Ritting S, Corydon TJ, Andreasen, PH, Jensen TG, Andresen BS, Robertson GL, Gregsen N, Bolund L, Pedersen EB . Clinical and molecular evidence of abnormal processing and traffiking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation J Clin Endocrinol Metab 1999 84: 2933–2941.

    CAS  PubMed  Google Scholar 

  25. Beuret N, Rutishauser J, Bider MD, Spiess M . Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus J Biol Chem 1999 274: 18965–18972.

    Article  CAS  PubMed  Google Scholar 

  26. Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S . A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with atosomal recessive familial isolated hypoparathyroidism J Clin Endocrinol Metab 1999 84: 3792–3796.

    CAS  PubMed  Google Scholar 

  27. O'Donohue TL, Dorsa DM . The opiomelanotropinergic neuronal and endocrine systems Peptides 1982 3: 353–395.

    Article  CAS  PubMed  Google Scholar 

  28. Giugliano D, Lefebvre PJ . A role for beta-endorphin in the pathogenesis of human obesity? Horm Metab Res 1991 23: 251–256.

    Article  CAS  PubMed  Google Scholar 

  29. Levinson G, Gutman GA . Slipped-strand mispairing: a major mechanism for DNA sequence evolution Mol Biol Evol 1987 4: 203–221.

    CAS  PubMed  Google Scholar 

  30. Pedersen RC, Brownie AC . Adrenocortical response to corticotropin is potentiated by part of the amino-terminal region of pro-opimelanocortin/endorphin Proc Nat Acad Sci USA 1980 77: 2239–2243.

    Article  CAS  PubMed  Google Scholar 

  31. Drouin J, Goodmen HM . Most of the coding region of rat ACTHβ-LPH precursor gene lacks intervening sequences Nature 1980 288: 610–613.

    Article  CAS  PubMed  Google Scholar 

  32. Morris JC, Savva D, Lowry PJ . Reduced expression of a naturally deleted form of human proopiomelanocortin complementary deoxyribonucleic acid after transfection into chinese hamster ovary cells Endocrinology 1995 136: 195–201.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Second University of Naples, Via S.Andrea delle Dame no. 4, Napoli, 80138, Italy

    E Miraglia del Giudice, G Cirillo, N Santoro, L D'Urso, MT Carbone, R Di Toro & L Perrone

Authors
  1. E Miraglia del Giudice
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Cirillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Santoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L D'Urso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. MT Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Di Toro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Perrone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Miraglia del Giudice.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miraglia del Giudice, E., Cirillo, G., Santoro, N. et al. Molecular screening of the proopiomelanocortin (POMC ) gene in Italian obese children: report of three new mutations. Int J Obes 25, 61–67 (2001). https://doi.org/10.1038/sj.ijo.0801485

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0801485

Keywords

This article is cited by

Search

Advanced search

Quick links