Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene

J Clin Endocrinol Metab. 2015 Sep;100(9):3227-30. doi: 10.1210/jc.2015-2263. Epub 2015 Jul 17.


Context: Congenital leptin deficiency is a very rare cause of severe early-onset obesity. We recently characterized a mutation in the leptin gene (p.D100Y), which was associated with detectable leptin levels and bioinactivity of the hormone.

Case description: We now describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia, both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin. In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive. Treatment with sc recombinant human leptin led to rapid improvement of eating behavior and weight loss.

Conclusions: Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Weight / genetics*
  • Child
  • Female
  • Humans
  • Hyperphagia / genetics*
  • Leptin / blood
  • Leptin / genetics*
  • Male
  • Mutation*
  • Obesity / genetics*


  • Leptin