Life (Basel)
Institute of Experimental Pediatric Endocrinology, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Published: November 2022
The () is critical for central satiety regulation, therefore presenting a potent target for pharmacological obesity treatment. 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 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 . 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, G and G 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 activation was almost impossible in W258X and Q307X with wild-type-like cell surface expression. Results for G signaling were comparable. Based on our data, this approach improbably represents a therapeutic option.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9697516 | PMC |
http://dx.doi.org/10.3390/life12111793 | DOI Listing |
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