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- Title
Characterization of the melanocortin-4-receptor nonsense mutation W16X in vitro and in vivo.
- Authors
Bolze, F; Rink, N; Brumm, H; Kühn, R; Mocek, S; Schwarz, A-E; Kless, C; Biebermann, H; Wurst, W; Rozman, J; Klingenspor, M
- Abstract
Several genetic diseases are triggered by nonsense mutations leading to the formation of truncated and defective proteins. Aminoglycosides have the capability to mediate a bypass of stop mutations during translation thus resulting in a rescue of protein expression. So far no attention has been directed to obesity-associated stop mutations as targets for nonsense suppression. Herein, we focus on the characterization of the melanocortin-4-receptor (MC4R) nonsense allele W16X identified in obese subjects. Cell culture assays revealed a loss-of-function of Mc4rX16 characterized by impaired surface expression and defect signaling. The aminoglycoside G-418 restored Mc4rX16 function in vitro demonstrating that Mc4rX16 is susceptible to nonsense suppression. For the evaluation of nonsense suppression in vivo, we generated a Mc4rX16 knock-in mouse line by gene targeting. Mc4rX16 knock-in mice developed hyperphagia, impaired glucose tolerance, severe obesity and an increased body length demonstrating that this new mouse model resembles typical characteristics of Mc4r deficiency. In a first therapeutic trial, the aminoglycosides gentamicin and amikacin induced no amelioration of obesity. Further experiments with Mc4rX16 knock-in mice will be instrumental to establish nonsense suppression for Mc4r as an obesity-associated target gene expressed in the central nervous system.
- Subjects
MELANOCORTIN receptors; GENETIC mutation; AMINOGLYCOSIDES; GENE expression; NONSENSE suppression (Genetics); GENTAMICIN; GENE targeting
- Publication
Pharmacogenomics Journal, 2013, Vol 13, Issue 1, p80
- ISSN
1470-269X
- Publication type
Article
- DOI
10.1038/tpj.2011.43