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Voigtmann, F.* ; Wolf, P.* ; Landgraf, K.* ; Stein, R. ; Kratzsch, J.* ; Schmitz, S.* ; Abou Jamra, R.* ; Blüher, M. ; Meiler, J.* ; Beck-Sickinger, A.G.* ; Kiess, W.* ; Körner, A.*

Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity.

Metabolism 116:154438 (2021)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Background: Deficiency in the leptin-leptin receptor (LEPR) axis leads to severe, and potentially treatable, obesity in humans. To guide clinical decision-making, the functional relevance of variants in the LEPR gene needs to be carefully investigated. Cases and methods: We characterized the functional impact of LEPR variants identified in two patients with severe early-onset obesity (1: compound heterozygous for the novel variant p.Tyr411del and p.Trp664Arg; 2: heterozygous for p.Arg612His) by investigating leptin-mediated signaling, leptin binding, receptor expression on cell surfaces, and receptor dimerization and activation for either wild-type and/or mutant LEPR. Results: Leptin-induced STAT3-phosphorylation was blunted the novel p.Tyr411del or the p.Trp664Arg variant and mildly reduced with the p.Arg612His variant. Computational structure prediction suggested impaired leptin binding for all three LEPR variants. Experimentally, reduced leptin binding of all mutant proteins was due to diminished LEPR expression on the cell surface, with the p.Trp664Arg mutations being the most affected. Considering the heterozygosity in our patients, we assessed the heterodimerization capacity with the wild-type LEPR, which was retained for the p.Tyr411del and p.Arg612His variants. Finally, mimicking (compound) heterozygosity, we confirmed abolished STAT3-phosphorylation for the variant combination [p.Tyr411del + p.Trp664Arg] as found in patient 1, whereas it was retained for [p.Arg612His + wilde type] as found in patient 2. Conclusions: The novel p.Tyr411del mutation causes complete loss of function alone (and combined with p.Trp664Arg) and is likely the cause for the early onset obesity, qualifying the patient for pharmacologic treatment. Heterozygosity for the p.Arg612His variant, however, appears unlikely to be solely responsible for the phenotype.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Case Report ; Childhood Obesity ; Genetic Variants ; Leptin Receptor ; Monogenic Obesity ; Setmelanotide
ISSN (print) / ISBN 0026-0495
e-ISSN 1532-8600
Quellenangaben Band: 116, Heft: , Seiten: , Artikelnummer: 154438 Supplement: ,
Verlag Elsevier
Verlagsort 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen FCI
DFG
Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum Munchen at the University of Leipzig
Clinician Scientist Programme of the Medical Faculty at the University of Leipzig
NIH NIGMS
graduate school BuildMoNa
German Diabetes Association (DDG)
German Federal Ministry of Education and Research (BMBF)
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)