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.