Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene
Schnurbein, Julia von
Journal of Clinical Endocrinology & Metabolism
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Wabitsch, M., Funcke, J., Schnurbein, J. v., Denzer, F., Lahr, G., Mazen, I., El-Gammal, M., et al. (2015). Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene. Journal of Clinical Endocrinology & Metabolism, 100 3227-3230. https://doi.org/10.1210/jc.2015-2263
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. Congenital leptin deficiency is characterized by hyperphagia and severe early-onset obesity, along with metabolic and endocrine derangements and in some cases also immunological alterations (1–3). The disease is caused by mutations in the LEP gene typically leading to defects in protein synthesis or secretion, and therefore to the absence or very low levels of the hormone in the circulation (1, 2). Recently, we described the first case of functional leptin deficiency (4). This entity is characterized by detectable immunoreactive levels of circulating leptin, but bioinactivity of the hormone due to defective receptor binding (4). We now describe two additional cases of functional leptin deficiency due to a c.309C>A substitution in the LEP gene resulting in an asparagine to lysine amino acid exchange at position 103 of the protein (p.N103K).
This work was supported by Grant BMBF 01GI1120A from the Federal Ministry of Education and Research. Support was also provided by the Wellcome Trust (082390/Z/07/Z), the Medical Research Council, the National Institute for Health Research Cambridge Biomedical Research Centre, the European Research Council, and the Bernard Wolfe Health Neuroscience Fund (all to I.S.F.). J.-B.F. was supported by the International Graduate School in Molecular Medicine Ulm.
Wellcome Trust (082390/Z/07/Z)
External DOI: https://doi.org/10.1210/jc.2015-2263
This record's URL: https://www.repository.cam.ac.uk/handle/1810/251446
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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