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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.
AuthorsMartin Wabitsch, Jan-Bernd Funcke, Belinda Lennerz, Ursula Kuhnle-Krahl, Georgia Lahr, Klaus-Michael Debatin, Petra Vatter, Peter Gierschik, Barbara Moepps, Pamela Fischer-Posovszky
JournalThe New England journal of medicine (N Engl J Med) Vol. 372 Issue 1 Pg. 48-54 (Jan 01 2015) ISSN: 1533-4406 [Electronic] United States
PMID25551525 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Leptin
  • Receptors, Leptin
  • metreleptin
Topics
  • Age of Onset
  • Animals
  • Body Mass Index
  • Cells, Cultured
  • Child, Preschool
  • Feeding Behavior (drug effects)
  • Female
  • Humans
  • Leptin (analogs & derivatives, deficiency, genetics, metabolism, therapeutic use)
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mutation
  • Obesity (drug therapy, genetics)
  • Receptors, Leptin (metabolism)
  • Sequence Analysis, DNA

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