Journal
NATURE METABOLISM
Volume 4, Issue 12, Pages 1697-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-022-00703-9
Keywords
-
Categories
Funding
- German Research Foundation [SFB1052/CRC1052, 209933838, KO3512/3-1]
- German Diabetes Association
- joint Clinician Scientist Program of the Medical Faculty
- Helmholtz Institute for Metabolic, Obesity and Vascular Research of the Helmholtz Zentrum Munchen at the University of Leipzig
Ask authors/readers for more resources
We report a heterozygous tandem duplication in the ASIP gene locus that causes widespread ectopic expression of ASIP in a female patient with extreme childhood obesity. Our data indicate that this ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available