Details zur Publikation

Kategorie Textpublikation
Referenztyp Zeitschriften
DOI 10.1038/s42255-022-00703-9
Lizenz creative commons licence
Titel (primär) Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity
Autor Kempf, E.; Landgraf, K.; Stein, R.; Hanschkow, M.; Hilbert, A.; Abou Jamra, R.; Boczki, P.; Herberth, G. ORCID logo ; Kühnapfel, A.; Tseng, Y.-H.; Stäubert, C.; Schöneberg, T.; Kühnen, P.; Rayner, N.W.; Zeggini, E.; Kiess, W.; Blüher, M.; Körner, A.
Quelle Nature Metabolism
Erscheinungsjahr 2022
Department IMMU
Band/Volume 4
Seite von 1697
Seite bis 1712
Sprache englisch
Topic T9 Healthy Planet
Keywords Gene regulation; Metabolic syndrome; Metabolism; Obesity; Paediatric research
Abstract 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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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. (2022):
Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity
Nat. Metab. 4 , 1697 - 1712 10.1038/s42255-022-00703-9