70 research outputs found
Final Report of the ASCOBANS Intersessional Working Group on the Assessment of Acoustic Disturbance
Homogenous Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope and Mechanistic Studies
The epidemiology of osteoporosis - Bone Evaluation Study (BEST): An analysis of routine health insurance data | Epidemiologie der Osteoporose: Bone Evaluation Study Eine Analyse von Krankenkassen-Routinedaten
Characterization of the melanocortin-4-receptor nonsense mutation W16X in vitro and in vivo
Characterization of the melanocortin-4-receptor nonsense mutation W16X <em>in vitro</em> and <em>in vivo</em>.
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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