Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor
I. Sadaf Farooqi, M.B., B.S., Ph.D., Teresia Wangensteen, M.D., Stephan Collins, Ph.D., Wendy Kimber, Ph.D., Giuseppe Matarese, M.D., Ph.D., Julia M. Keogh, B.Sc., Emma Lank, B.Sc., Bill Bottomley, Ph.D., Judith Lopez-Fernandez, M.D., Ph.D., Ivan Ferraz-Amaro, M.D., Ph.D., Mehul T. Dattani, M.D., Oya Ercan, M.D., Anne Grethe Myhre, M.D., Lars Retterstol, M.D., Ph.D., Richard Stanhope, M.D., Julie A. Edge, M.B., B.S., Sheila McKenzie, M.B., B.S., Nader Lessan, M.B., B.S., Maryam Ghodsi, M.B., B.S., Veronica De Rosa, Ph.D., Francesco Perna, M.D., Silvia Fontana, Ph.D., Inês Barroso, Ph.D., Dag E. Undlien, M.D., Ph.D., and Stephen O'Rahilly, M.D.
Background A single family has been described in which obesityresults from a mutation in the leptin-receptor gene (LEPR),but the prevalence of such mutations in severe, early-onsetobesity has not been systematically examined.
Methods We sequenced LEPR in 300 subjects with hyperphagia andsevere early-onset obesity, including 90 probands from consanguineousfamilies, and investigated the extent to which mutations cosegregatedwith obesity and affected receptor function. We evaluated metabolic,endocrine, and immune function in probands and affected relatives.
Results Of the 300 subjects, 8 (3%) had nonsense or missenseLEPR mutations — 7 were homozygotes, and 1 was a compoundheterozygote. All missense mutations resulted in impaired receptorsignaling. Affected subjects were characterized by hyperphagia,severe obesity, alterations in immune function, and delayedpuberty due to hypogonadotropic hypogonadism. Serum leptin levelswere within the range predicted by the elevated fat mass inthese subjects. Their clinical features were less severe thanthose of subjects with congenital leptin deficiency.
Conclusions The prevalence of pathogenic LEPR mutations in acohort of subjects with severe, early-onset obesity was 3%.Circulating levels of leptin were not disproportionately elevated,suggesting that serum leptin cannot be used as a marker forleptin-receptor deficiency. Congenital leptin-receptor deficiencyshould be considered in the differential diagnosis in any childwith hyperphagia and severe obesity in the absence of developmentaldelay or dysmorphism.
Source Information
From the Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge (I.S.F., W.K., J.M.K., E.L., S.O.); the Wellcome Trust Sanger Institute, Cambridgeshire (S.C., B.B., I.B.); the Institute of Child Health, London (M.T.D.); Great Ormond Street Hospital and University College London, London (R.S.); John Radcliffe Hospital, Oxford (J.A.E.); and Royal London Hospital, London (S.M.) — all in the United Kingdom; Ulleval University Hospital, University of Oslo (T.W., L.R., D.E.U.), and Rikshospitalet–Radiumhospitalet Medical Center (A.G.M.) — both in Oslo; Università di Napoli "Frederico II" (G.M., V.D.R., F.P.) and Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (G.M., V.D.R., S.F.) — both in Naples, Italy; Hospital Universitario de Canarias, Tenerife, Spain (J.L.-F., I.F.-A.); the Istanbul University Cerrahpasa Medical Faculty, Fatih Istanbul, Turkey (O.E.); and Tehran University of Medical Sciences Shariati Hospital, Tehran, Iran (N.L., M.G.).
Address reprint requests to Dr. Farooqi at the University Department of Clinical Biochemistry, Addenbrooke's Hospital, Hills Rd., Box 232, Cambridge CB2 2QQ, United Kingdom, or at isf20{at}cam.ac.uk.
Lee, D.-E., Kehlenbrink, S., Lee, H., Hawkins, M., Yudkin, J. S.
(2009). Getting the message across: mechanisms of physiological cross talk by adipose tissue. Am. J. Physiol. Endocrinol. Metab.
296: E1210-E1229
[Abstract][Full Text]
Reinwald, S., Peterson, R. G., Allen, M. R., Burr, D. B.
(2009). Skeletal changes associated with the onset of type 2 diabetes in the ZDF and ZDSD rodent models. Am. J. Physiol. Endocrinol. Metab.
296: E765-E774
[Abstract][Full Text]
Calton, M. A., Ersoy, B. A., Zhang, S., Kane, J. P., Malloy, M. J., Pullinger, C. R., Bromberg, Y., Pennacchio, L. A., Dent, R., McPherson, R., Ahituv, N., Vaisse, C.
(2009). Association of functionally significant Melanocortin-4 but not Melanocortin-3 receptor mutations with severe adult obesity in a large North American case-control study. Hum Mol Genet
18: 1140-1147
[Abstract][Full Text]
Bluher, S., Mantzoros, C. S
(2009). Leptin in humans: lessons from translational research. Am. J. Clin. Nutr.
89: 991S-997S
[Abstract][Full Text]
Friedman, J. M
(2009). Leptin at 14 y of age: an ongoing story. Am. J. Clin. Nutr.
89: 973S-979S
[Abstract][Full Text]
Farooqi, I S., O'Rahilly, S.
(2009). Leptin: a pivotal regulator of human energy homeostasis. Am. J. Clin. Nutr.
89: 980S-984S
[Abstract][Full Text]
Hill, M J, Kumar, S, McTernan, P G
(2009). Adipokines and the clinical laboratory: what to measure, when and how?. J. Clin. Pathol.
62: 206-211
[Abstract][Full Text]
Munoz, G., Ovilo, C., Silio, L., Tomas, A., Noguera, J. L., Rodriguez, M. C.
(2009). Single- and joint-population analyses of two experimental pig crosses to confirm quantitative trait loci on Sus scrofa chromosome 6 and leptin receptor effects on fatness and growth traits. J ANIM SCI
87: 459-468
[Abstract][Full Text]
Kimber, W., Peelman, F., Prieur, X., Wangensteen, T., O'Rahilly, S., Tavernier, J., Farooqi, I. S.
(2008). Functional Characterization of Naturally Occurring Pathogenic Mutations in the Human Leptin Receptor. Endocrinology
149: 6043-6052
[Abstract][Full Text]
O'Rahilly, S., Farooqi, I. S.
(2008). Human Obesity: A Heritable Neurobehavioral Disorder That Is Highly Sensitive to Environmental Conditions. Diabetes
57: 2905-2910
[Full Text]
Rasouli, N., Kern, P. A.
(2008). Adipocytokines and the Metabolic Complications of Obesity. J. Clin. Endocrinol. Metab.
93: s64-s73
[Abstract][Full Text]
Unger, R. H.
(2008). Noninvasive tracking of gene expression by reporter transgene imaging. Proc. Natl. Acad. Sci. USA
105: 12641-12642
[Full Text]
Chan, J. L., Williams, C. J., Raciti, P., Blakeman, J., Kelesidis, T., Kelesidis, I., Johnson, M. L., Thorner, M. O., Mantzoros, C. S.
(2008). Leptin Does Not Mediate Short-Term Fasting-Induced Changes in Growth Hormone Pulsatility but Increases IGF-I in Leptin Deficiency States. J. Clin. Endocrinol. Metab.
93: 2819-2827
[Abstract][Full Text]
Bessesen, D. H.
(2008). Update on Obesity. J. Clin. Endocrinol. Metab.
93: 2027-2034
[Abstract][Full Text]
Mark, A. L.
(2008). Dietary Therapy for Obesity: An Emperor With No Clothes. Hypertension
51: 1426-1434
[Full Text]
Crowley, V. E F
(2008). Overview of human obesity and central mechanisms regulating energy homeostasis. Ann Clin Biochem
45: 245-255
[Abstract][Full Text]
Taleb, S., Herbin, O., Ait-Oufella, H., Verreth, W., Gourdy, P., Barateau, V., Merval, R., Esposito, B., Clement, K., Holvoet, P., Tedgui, A., Mallat, Z.
(2007). Defective Leptin/Leptin Receptor Signaling Improves Regulatory T Cell Immune Response and Protects Mice From Atherosclerosis. Arterioscler. Thromb. Vasc. Bio.
27: 2691-2698
[Abstract][Full Text]
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