DOC PREVIEW
Stanford BIO 230 - Lecture Notes

This preview shows page 1-2-3-4 out of 11 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 11 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 11 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 11 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 11 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 11 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

T h e n e w e ngl a n d j o u r na l o f m e dic i n en engl j med 356;3 www.nejm.org january 18, 2007237original articleClinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin ReceptorI. 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.From the Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cam-bridge (I.S.F., W.K., J.M.K., E.L., S.O.); the Wellcome Trust Sanger Institute, Cam-bridgeshire (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 Rad-cliffe 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–Radiumhospi-talet Medical Center (A.G.M.) — both in Oslo; Università di Napoli “Frederico II” (G.M., V.D.R., F.P.) and Istituto di Endo-crinologia e Oncologia Sperimentale, Con-siglio Nazionale delle Ricerche (G.M., V.D.R., S.F.) — both in Naples, Italy; Hos-pital Universitario de Canarias, Tenerife, Spain (J.L.-F., I.F.-A.); the Istanbul Uni-versity Cerrahpasa Medical Faculty, Fatih Istanbul, Turkey (O.E.); and Tehran Uni-versity of Medical Sciences Shariati Hos-pital, Tehran, Iran (N.L., M.G.). Address reprint requests to Dr. Farooqi at the Uni-versity Department of Clinical Biochem-istry, Addenbrooke’s Hospital, Hills Rd., Box 232, Cambridge CB2 2QQ, United Kingdom, or at [email protected] Engl J Med 2007;356:237-47.Copyright © 2007 Massachusetts Medical Society. A B S T R AC TBACKGROUNDA single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined.METHODSWe sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evalu-ated metabolic, endocrine, and immune function in probands and affected relatives.RESULTSOf the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations — 7 were ho-mozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogo-nadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency.CONCLUSIONSThe prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevat-ed, suggesting that serum leptin cannot be used as a marker for leptin-receptor defi-ciency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of devel-opmental delay or dysmorphism.Copyright © 2007 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at LANE MEDICAL LIBRARY on October 28, 2007 .T h e n e w e ngl a nd j o u r na l o f m e d ic i nen engl j med 356;3 www.nejm.org january 18, 2007238T he assessment of patients with se-vere early-onset obesity conventionally in-cludes screening for potentially treatable neurologic and endocrine conditions and identi-fying known genetic conditions so that appropri-ate genetic counseling and, in some cases, treat-ment can be instituted.1 Classically, patients with genetic obesity syndromes have been identified in childhood as a result of associated mental retarda-tion and developmental abnormalities.2 However, several monogenic disorders have been identified in which obesity itself is the predominant present-ing feature. These disorders result from disruption of the hypothalamic leptin–melanocortin signaling pathway.3-8Twelve subjects with congenital leptin defi-ciency due to loss-of-function mutations in the gene encoding leptin have been identified3,4,9,10 (and unpublished data). Characteristic features in-clude hyperphagia, obesity, hypogonadism, and impaired T-cell–mediated immunity. Treatment with recombinant human leptin reverses all as-pects of the phenotype.9,11,12 So far, only one mu-tation in the leptin-receptor gene (LEPR) has been reported, in three severely obese adult siblings from a consanguineous family of Algerian origin.5 This mutation results in abnormal splicing of leptin-receptor transcripts and generates a mutant leptin receptor that lacks both transmembrane and intracellular domains. The mutant receptor circu-lates at high concentrations, binding leptin and resulting in very elevated serum leptin levels.13 To determine the prevalence of pathogenic mutations in LEPR in severely obese patients, we studied 300 subjects with severe, early-onset obesity.M e t h od sSubjectsWhen we began the study, the Genetics of Obesity Study (GOOS) cohort consisted of 2100 unrelated probands with severe obesity of early onset (before 10 years of age); severe obesity was defined as a standard-deviation score for the body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of more than 3. We calculated BMI standard-deviation scores using ref-erence data from the U.K. population.14 The mean (±SD) score in the GOOS cohort is 4.2±0.8. Of the 2100 subjects, 1800 were reported to have a history of hyperphagia. Of these 1800 subjects, 300 were selected to determine the prevalence of leptin-receptor mutations: all 90 subjects in the GOOS cohort from consanguineous families, as well as


View Full Document

Stanford BIO 230 - Lecture Notes

Documents in this Course
Load more
Download Lecture Notes
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view Lecture Notes and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Lecture Notes 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?