Leptin Gene Mutation Linked to Early-Onset Obesity

(HealthDay News) — A mutation in the gene encoding leptin (LEP) resulting in biologically inactive leptin can cause early-onset extreme obesity, according to a brief report published in the New England Journal of Medicine.

Martin Wabitsch, MD, PhD, from the University of Ulm in Germany, and colleagues describe a case of a 2-year-old boy with early-onset extreme obesity.

Using standard protocols for LEP sequencing on genomic DNA, the researchers identified a novel homozygous transversion (c.298G→T). This resulted in a change from aspartic acid to tyrosine at amino acid position 100 (p.D100Y). 

The patient had high circulating levels of mutant leptin, which was unable to bind to or activate the leptin receptor. In leptin deficient ob/ob mice, the mutant protein failed to reduce food intake and body weight. Eating behavior was rapidly normalized in the patient when treated with recombinant human leptin (metreleptin), resulting in weight loss.

“Given our findings, circulating levels of the hormone that appear to be normal in relation to body mass index and fat mass do not rule out disease-causing mutations in the gene encoding leptin and might obscure the correct diagnosis,” the researchers wrote.

Metreleptin was provided by Amylin Pharmaceuticals, Bristol-Myers Squibb, and AstraZeneca.


  1. Wabitsch M et al. N Engl J Med. 2015;372:48-54.