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Kempf, E.* ; Landgraf, K.* ; Stein, R. ; Hanschkow, M.* ; Hilbert, A.* ; Abou Jamra, R.* ; Boczki, P.* ; Herberth, G.* ; Kühnapfel, A.* ; Tseng, Y.H.* ; Stäubert, C.* ; Schöneberg, T.* ; Kühnen, P.* ; Rayner, N.W. ; Zeggini, E. ; Kiess, W.* ; Blüher, M. ; Körner, A.

Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity.

Nat. Metab. 4, 1697-1712 (2022)
Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Here we report a heterozygous tandem duplication at the ASIP (agouti signaling protein) gene locus causing ubiquitous, ectopic ASIP expression in a female patient with extreme childhood obesity. The mutation places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase promoter, driving the generation of ASIP in patient-derived native and induced pluripotent stem cells for all germ layers and hypothalamic-like neurons. The patient’s phenotype of early-onset obesity, overgrowth, red hair and hyperinsulinemia is concordant with that of mutant mice ubiquitously expressing the homolog nonagouti. ASIP represses melanocyte-stimulating hormone-mediated activation as a melanocortin receptor antagonist, which might affect eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the index patient. As the type of mutation escapes standard genetic screening algorithms, we rescreened the Leipzig Childhood Obesity cohort of 1,745 patients and identified four additional patients with the identical mutation, ectopic ASIP expression and a similar phenotype. Taken together, our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Body-mass Index; Gene; Association; Mutations; Receptor; Stringtie; Variants; Agonist; Genome; Mouse
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Quellenangaben Volume: 4, Issue: 12, Pages: 1697-1712 Article Number: , Supplement: ,
Publisher Springer
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Institute of Translational Genomics (ITG)
Grants Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum Munchen at the University of Leipzig
joint Clinician Scientist Program of the Medical Faculty
German Diabetes Association
German Research Foundation