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.
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