Publication Details

Category Text Publication
Reference Category Journals
DOI 10.1038/s42255-022-00703-9
Licence creative commons licence
Title (Primary) Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity
Author 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.
Source Titel Nature Metabolism
Year 2022
Department IMMU
Volume 4
Page From 1697
Page To 1712
Language 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.
Persistent UFZ Identifier
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