PuSH - Publication Server of Helmholtz Zentrum München

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)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
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
Journal Pharmacogenomics Journal, The
Quellenangaben Volume: 13, Issue: 1, Pages: 80-93 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
Institute of Experimental Genetics (IEG)