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Bolze, F.* ; Rink, N.* ; Brumm, H.* ; Kühn, R. ; Mocek, S.* ; Schwarz, A.E. ; Kless, C.* ; Biebermann, H.* ; Wurst, W. ; Rozman, J. ; Klingenspor, M.*

Characterization of the melanocortin-4-receptor nonsense mutation W16X in vitro and in vivo.

Pharmacogenomics J. 13, 80-93 (2013)
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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 Mc4r(X16) characterized by impaired surface expression and defect signaling. The aminoglycoside G-418 restored Mc4r(X16) function in vitro demonstrating that Mc4r(X16) is susceptible to nonsense suppression. For the evaluation of nonsense suppression in vivo, we generated a Mc4r(X16) knock-in mouse line by gene targeting. Mc4r(X16) 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 Mc4r(X16) knock-in mice will be instrumental to establish nonsense suppression for Mc4r as an obesity-associated target gene expressed in the central nervous system.
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Publication type Article: Journal article
Document type Scientific Article
Keywords melanocortin-4-receptor; Obesity; Nonsense suppression; Aminoglycosides; Mammalian Translation System ; Agouti-related Protein ; Cerebrospinal-fluid ; Metabolic-rate ; Leptin Receptor ; Stop Mutation ; Mdx Mice ; Obesity ; Gene ; Suppression
ISSN (print) / ISBN 1470-269X
e-ISSN 1473-1150
Quellenangaben Volume: 13, Issue: 1, Pages: 80-93 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Reviewing status Peer reviewed