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| Item Type: | Article |
|---|---|
| Title: | Evaluation of pharmacological rescue of melanocortin-4 receptor nonsense mutations by aminoglycoside |
| Creators Name: | Höpfner, F. and Paisdzior, S. and Reininghaus, N. and Sohail, I. and Scheerer, P. and Annibale, P. and Biebermann, H. and Kühnen, P. |
| Abstract: | The melanocortin-4 receptor (MC4R) is critical for central satiety regulation, therefore presenting a potent target for pharmacological obesity treatment. Melanocortin-4 receptor mutations prevalently cause monogenetic obesity. A possibility of overcoming stop mutations is aminoglycoside-mediated translational readthrough. Promising results were achieved in COS-7 cells, but data for human cell systems are still missing, so uncertainty surrounds this potential treatment. In transfected HEK-293 cells, we tested whether translational readthrough by aminoglycoside Geneticin combined with high-affinity ligand setmelanotide, which is effective in proopiomelanocortin or leptin receptor deficiency patients, is a treatment option for affected patients. Five MC4R nonsense mutants (W16X, Y35X_D37V, E61X, W258X, Q307X) were investigated. Confocal microscopy and cell surface expression assays revealed the importance of the mutations' position within the MC4R. N-terminal mutants were marginally expressed independent of Geneticin treatment, whereas mutants with nonsense mutations in transmembrane helix 6 or helix 8 showed wild-type-like expression. For functional analysis, Gs and G(q/11) signaling were measured. N-terminal mutants (W16X, Y35X_D37V) showed no cAMP formation after challenge with alpha-MSH or setmelanotide, irrespective of Geneticin treatment. Similarly, G(s) activation was almost impossible in W258X and Q307X with wild-type-like cell surface expression. Results for G(q/11) signaling were comparable. Based on our data, this approach improbably represents a therapeutic option. |
| Keywords: | Melanocortin 4 Receptor, MC4R, Stop Mutation, PTC, Translational Readthrough, G418 |
| Source: | Life |
| ISSN: | 2075-1729 |
| Publisher: | MDPI |
| Volume: | 12 |
| Number: | 11 |
| Page Range: | 1793 |
| Date: | 5 November 2022 |
| Official Publication: | https://doi.org/10.3390/life12111793 |
| PubMed: | View item in PubMed |
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