High prevalence of leptin and melanocortin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families

Molecular Genetics and Metabolism

Volumn 106, Issue 1, 2012, Pages 121-126

  Saeed, Sadia ^a   Butt, Taeed A ^b   Anwer, Mehwish ^c   Arslan, Muhammad ^d   Froguel, Philippe ^a,e  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

^b CHILDREN S HOSPITAL   (Pakistan)

^c UNIVERSITY OF LAHORE   (Pakistan)

^d FORMAN CHRISTIAN COLLEGE A CHARTERED UNIVERSITY   (Pakistan)

^e UNIV LILLE   (France)

Author keywords

Congenital leptin deficiency; Consanguinity; LEP; MC4R; Monogenic obesity

Indexed keywords

HYDROCORTISONE; INSULIN; LEPTIN; MELANOCORTIN 4 RECEPTOR; THYROTROPIN;

ARTICLE; BODY WEIGHT; CHILD; COHORT ANALYSIS; CONSANGUINEOUS MARRIAGE; CONTROLLED STUDY; DISEASE SEVERITY; FEMALE; GENE MUTATION; GENETIC ASSOCIATION; GENETIC CODE; HUMAN; HYDROCORTISONE BLOOD LEVEL; HYPERINSULINEMIA; HYPERLEPTINEMIA; HYPERPHAGIA; INFANT; INSULIN BLOOD LEVEL; MALE; OBESITY; PAKISTAN; PRESCHOOL CHILD; PRIORITY JOURNAL; SCHOOL CHILD; THYROTROPIN BLOOD LEVEL;

ADOLESCENT; CHILD; CHILD, PRESCHOOL; FEMALE; HUMANS; HYDROCORTISONE; INFANT; INSULIN; LEPTIN; MALE; MUTATION; OBESITY; PAKISTAN; PEDIGREE; RECEPTOR, MELANOCORTIN, TYPE 4;

EID: 84860211766     PISSN: 10967192     EISSN: 10967206     Source Type: Journal    
DOI: 10.1016/j.ymgme.2012.03.001     Document Type: Article

References (30)

1. Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J.M. Positional cloning of the mouse obese gene and its human homologue. Nature 1994, 372:425-432.
2. Walley A.J., Asher J.E., Froguel P. The genetic contribution to non-syndromic human obesity. Nat. Rev. Genet. 2009, 10:431-442.
3. Blakemore A.I., Froguel P. Investigation of Mendelian forms of obesity holds out the prospect of personalized medicine. Ann. N. Y. Acad. Sci. 2010, 1214:180-189.
4. Montague C.T., Farooqi I.S., Whitehead J.P., Soos M.A., Rau H., Wareham N.J., Sewter C.P., Digby J.E., Mohammed S.N., Hurst J.A., Cheetham C.H., Earley A.R., Barnett A.H., Prins J.B., O'Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997, 387:903-908.
5. Strobel A., Issad T., Camoin L., Ozata M., Strosberg A.D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat. Genet. 1998, 18:213-215.
6. Gibson W.T., Farooqi I.S., Moreau M., DePaoli A.M., Lawrence E., O'Rahilly S., Trussell R.A. 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, 89:4821-4826.
7. 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, 97:305-308.
8. Fischer-Posovszky P., von Schnurbein J., Moepps B., Lahr G., Strauss G., Barth T.F., Kassubek J., Mühleder H., Möller P., Debatin K.M., Gierschik P., Wabitsch M. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. J. Clin. Endocrinol. Metab. 2010, 95:2836-2840.
9. O'Rahilly S. Human obesity and insulin resistance: lessons from experiments of nature. Biochem. Soc. Trans. 2007, 35(Pt 1):33-36.
10. Ozata M., Ozdemir I.C., Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J. Clin. Endocrinol. Metab. 1999, 84:3686-3695.
11. Paz-Filho G.J., Babikian T., Asarnow R., Delibasi T., Esposito K., Erol H.K., Wong M.L., Licinio J. Leptin replacement improves cognitive development. PLoS One 2008, 3:e3098.
12. Fatima W., Shahid A., Imran M., Manzoor J., Hasnain S., Rana S., Mahmood S. Leptin deficiency and leptin gene mutations in obese children from Pakistan. Int. J. Pediatr. Obes. 2011, 6:419-4127.
13. Farooqi I.S., Keogh J.M., Yeo G.S., Lank E.J., Cheetham T., O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 2003, 348:1085-1095.
14. Stutzmann F., Tan K., Vatin V., Dina C., Jouret B., Tichet J., Balkau B., Potoczna N., Horber F., O'Rahilly S., Farooqi I.S., Froguel P., Meyre D. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 2008, 57:2511-2518.
15. Hashmi M.A. Frequency of consanguinity and its effect on congenital malformation-a hospital based study. J. Pak. Med. Assoc. 1997, 47:75-78.
16. Woods C.G., Cox J., Springell K., Hampshire D.J., Mohamed M.D., McKibbin M., Stern R., Raymond F.L., Sandford R., Malik Sharif S., Karbani G., Ahmed M., Bond J., Clayton D., Inglehearn C.F. Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am. J. Hum. Genet. 2006, 78:889-896.
17. Hussain R., Bittles A.H. The prevalence and demographic characteristics of consanguineous marriages in Pakistan. J. Biosoc. Sci. 1998, 30:261-275.
18. Ibbetson D. Panjab Castes (being a reprint of the chapter on the races, castes and tribes of the people in the report on the Census of the Panjab published in 1883 by the late Sir Denzil Ibbetson) 1916, Government Printing, Lahore.
19. Shaw A. Kinship, cultural preference and immigration: consanguineous marriage among British Pakistanis. J. R. Anthropol. Inst. 2001, 7:315-334.
20. Shami S.A., Grant J.C., Bittles A.H. Consanguineous marriage within social/occupational class boundaries in Pakistan. J. Biosoc. Sci. 1994, 26:91-96.
21. Tao Y.X. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr. Rev. 2010, 31:506-543.
22. Larsen L.H., Echwald S.M., Sorensen T.I., Andersen T., Wulff B.S., Pedersen O. Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. J. Clin. Endocrinol. Metab. 2005, 90:219-224.
23. Tan K., Pogozheva I.D., Yeo G.S., Hadaschik D., Keogh J.M., Haskell-Leuvano C., O'Rahilly S., Mosberg H.I., Farooqi I.S. Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor. Endocrinology 2009, 150:114-125.
24. Martinelli C.E., Keogh J.M., Greenfield J.R., Henning E., van der Klaauw A.A., Blackwood A., O'Rahilly S., Roelfsema F., Camacho-Hübner C., Pijl H., Farooqi I.S. 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:E181-E188.
25. Yeo G.S., Lank E.J., Farooqi I.S., Keogh J., Challis B.G., O'Rahilly S. 2003 Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum. Mol. Genet. 2003, 12:561-574.
26. Dardeno T.A., Chou S.H., Moon H.S., Chamberland J.P., Fiorenza C.G., Mantzoros C.S. Leptin in human physiology and therapeutics. Front. Neuroendocrinol. 2010, 31:377-393.
27. Farooqi I.S., Matarese G., Lord G.M., Keogh J.M., Lawrence E., Agwu C., Sanna V., Jebb S.A., Perna F., Fontana S., Lechler R.I., DePaoli A.M., O'Rahilly S. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 2002, 110:1093-1103.
28. Paz-Filho G., Wong M.L., Licinio J. Ten years of leptin replacement therapy. Obes. Rev. 2011, 12:315-323.
29. Fan Z.C., Tao Y.X. Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients. J. Cell. Mol. Med. 2009, 13:3268-3282.
30. Roubert P., Dubern B., Plas P., Lubrano-Berthelier C., Alihi R., Auger F., Deoliveira D.B., Dong J.Z., Basdevant A., Thurieau C., Clément K. Novel pharmacological MC4R agonists can efficiently activate mutated MC4R from obese patient with impaired endogenous agonist response. J. Endocrinol. 2010, 207:177-183.