title: Biologically inactive leptin and early-onset extreme obesity.
abstract: Mutations in the gene encoding leptin (LEP) typically lead to an absence of circulating leptin and to extreme obesity. We describe a 2-year-old boy with early-onset extreme obesity due to a novel homozygous transversion (c.298G→T) in LEP, leading to a change from aspartic acid to tyrosine at amino acid position 100 (p.D100Y) and high immunoreactive levels of leptin. Overexpression studies confirmed that the mutant protein is secreted but neither binds to nor activates the leptin receptor. The mutant protein failed to reduce food intake and body weight in leptin-deficient ob/ob mice. Treatment of the patient with recombinant human leptin (metreleptin) rapidly normalized eating behavior and resulted in weight loss.
authors.affiliation: From the Division of Pediatric Endocrinology and Diabetes (M.W., J.-B.F., B.L., P.F.-P.), Department of Pediatrics and Adolescent Medicine (G.L., K.-M.D.), and the Institute of Pharmacology and Toxicology (P.V., P.G., B.M.), University of Ulm, Ulm; and Endokrinologische Schwerpunktpraxis für Kinder- und Jugendliche, Gauting (U.K.-K.) - both in Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Jan-Bernd
authors.initials: JB
authors.lastname: Funcke
authors.forename: Belinda
authors.initials: B
authors.lastname: Lennerz
authors.forename: Ursula
authors.initials: U
authors.lastname: Kuhnle-Krahl
authors.forename: Georgia
authors.initials: G
authors.lastname: Lahr
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Petra
authors.initials: P
authors.lastname: Vatter
authors.forename: Peter
authors.initials: P
authors.lastname: Gierschik
authors.forename: Barbara
authors.initials: B
authors.lastname: Moepps
authors.forename: Pamela
authors.initials: P
authors.lastname: Fischer-Posovszky
mesh_terms: D017668:Age of Onset; D000818:Animals; D015992:Body Mass Index; D002478:Cells, Cultured; D002675:Child, Preschool; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D006801:Humans; D020738:Leptin / Q000031:analogs & derivatives* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009765:Obesity / Q000188:drug therapy / Q000235:genetics*; D054411:Receptors, Leptin / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; C415771:metreleptin