{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:41:46Z","timestamp":1791207706256,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,9,10]],"date-time":"2012-09-10T00:00:00Z","timestamp":1347235200000},"content-version":"vor","delay-in-days":132,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Obesity"],"published-print":{"date-parts":[[2012,5]]},"abstract":"<jats:p>Aminoglycoside\u2010mediated read\u2010through of stop codons was recently demonstrated for a variety of diseases <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. About 30 percent of human genetic diseases are the consequence of nonsense mutations. Nonsense mutations in obesity\u2010associated genes like the melanocortin 4 receptor (<jats:italic>MC4R<\/jats:italic>), expressed in the hypothalamus, show the impact of premature stop codons on energy homeostasis. Therefore, the MC4R could be a potential pharmaceutical target for obesity treatment and targeting MC4R stop mutations could serve as proof of principle for nonsense mutations in genes expressed in the brain. We investigated four naturally occurring nonsense mutations in the <jats:italic>MC4R<\/jats:italic> (W16X, Y35X, E61X, Q307X) located at different positions in the receptor for aminoglycoside\u2010mediated functional rescue <jats:italic>in vitro<\/jats:italic>. We determined localization and amount of full\u2010length protein before and after aminoglycoside treatment by fluorescence microscopy, cell surface and total enzyme linked immunosorbent assay (ELISA). Signal transduction properties were analyzed by cyclic adenosine monophosphate (cAMP) assays after transient transfection of MC4R wild type and mutant receptors into COS\u20107 cells. Functional rescue of stop mutations in the MC4R is dependent on: (i) triplet sequence of the stop codon, (ii) surrounding sequence, (iii) location within the receptor, (iv) applied aminoglycoside and ligand. Functional rescue was possible for W16X, Y35X (N\u2010terminus), less successful for Q307X (C\u2010terminus) and barely feasible for E61X (first transmembrane domain). Restoration of full\u2010length proteins by PTC124 could not be confirmed. Future pharmaceutical applications must consider the potency of aminoglycosides to restore receptor function as well as the ability to pass the blood\u2010brain barrier.<\/jats:p>","DOI":"10.1038\/oby.2011.202","type":"journal-article","created":{"date-parts":[[2011,7,20]],"date-time":"2011-07-20T11:24:49Z","timestamp":1311161089000},"page":"1074-1081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Rescue of Melanocortin 4 Receptor (MC4R) Nonsense Mutations by Aminoglycoside\u2010Mediated 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