Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene
Martin Wabitsch1, Jan-Bernd Funcke1, Julia von Schnurbein1
1Division of Pediatric Endocrinology and Diabetes (M.W., J.-B.F., J.v.S., F.D., C.D., A.M., P.F.-P.), and Department of Pediatrics and Adolescent Medicine (G.L., K.-M.D.), University Medical Center Ulm, 89075 Ulm, Germany; Clinical Genetics Department (I.M., M.E.), National Research Center, Cairo 12311, Egypt; Institute of Pharmacology and Toxicology (P.G., B.M.), University Medical Center Ulm, 89081 Ulm, Germany; and University of Cambridge Metabolic Research Laboratories (V.M., J.M.K., I.S.F.), Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
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.
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