دورية أكاديمية
أعرض في EDS

The aminoglycoside geneticin permits translational readthrough of the CTNS W138X nonsense mutation in fibroblasts from patients with nephropathic cystinosis.

التفاصيل البيبلوغرافية
العنوان: The aminoglycoside geneticin permits translational readthrough of the CTNS W138X nonsense mutation in fibroblasts from patients with nephropathic cystinosis.
المؤلفون: Brasell EJ; Department of Human Genetics, McGill University, Montreal, Québec, Canada., Chu L; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Québec, Canada., El Kares R; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Québec, Canada., Seo JH; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Québec, Canada., Loesch R; L'Université Paris Descartes, Paris, France., Iglesias DM; Génome Québec, 630 Boulevard René-Lévesque, Montreal, Canada., Goodyer P; Department of Human Genetics, McGill University, Montreal, Québec, Canada. Paul.Goodyer@mcgill.ca.; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Québec, Canada. Paul.Goodyer@mcgill.ca.; Department of Experimental Medicine, McGill University, Montreal, Canada. Paul.Goodyer@mcgill.ca.
المصدر: Pediatric nephrology (Berlin, Germany) [Pediatr Nephrol] 2019 May; Vol. 34 (5), pp. 873-881. Date of Electronic Publication: 2018 Nov 09.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Springer International Country of Publication: Germany NLM ID: 8708728 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-198X (Electronic) Linking ISSN: 0931041X NLM ISO Abbreviation: Pediatr Nephrol Subsets: MEDLINE
أسماء مطبوعة: Publication: Berlin : Springer International
Original Publication: Berlin : Springer International, c1987-
مواضيع طبية MeSH: Amino Acid Transport Systems, Neutral/*genetics , Cystinosis/*drug therapy , Fibroblasts/*drug effects , Gentamicins/*pharmacology , Peptide Chain Termination, Translational/*drug effects, Codon, Nonsense ; Cystine/metabolism ; Cystinosis/genetics ; Fibroblasts/metabolism ; Genetic Vectors/genetics ; Gentamicins/therapeutic use ; HEK293 Cells ; Humans ; Peptide Chain Termination, Translational/genetics ; Plasmids/genetics ; RNA, Messenger/analysis ; Recombinant Proteins/genetics ; Transfection
مستخلص: Background: Cystinosis is an ultrarare disorder caused by mutations of the cystinosin (CTNS) gene, encoding a cystine-selective efflux channel in the lysosomes of all cells of the body. Oral therapy with cysteamine reduces intralysosomal cystine accumulation and slows organ deterioration but cannot reverse renal Fanconi syndrome nor prevent the eventual need for renal transplantation. A definitive therapeutic remains elusive. About 15% of cystinosis patients worldwide carry one or more nonsense mutations that halt translation of the CTNS protein. Aminoglycosides such as geneticin (G418) can bind to the mammalian ribosome, relax translational fidelity, and permit readthrough of premature termination codons to produce full-length protein.
Methods: To ascertain whether aminoglycosides permit readthrough of the most common CTNS nonsense mutation, W138X, we studied the effect of G418 on patient fibroblasts.
Results: G418 treatment induced translational readthrough of CTNS W138X constructs transfected into HEK293 cells and expression of full-length endogenous CTNS protein in homozygous W138X fibroblasts.
Conclusions: Reduction in intracellular cystine indicates that the CTNS protein produced is functional as a cystine transporter. Interestingly, similar effects were seen even in W138X compound heterozygotes. These studies establish proof-of-principle for the potential of aminoglycosides to treat cystinosis and possibly other monogenic diseases caused by nonsense mutations.
التعليقات: Comment in: Pediatr Nephrol. 2019 May;34(5):917-920. (PMID: 30623245)
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معلومات مُعتمدة: Canada CIHR
فهرسة مساهمة: Keywords: Aminoglycoside; Cystinosis; Geneticin; Nonsense mutation; Translational readthrough
المشرفين على المادة: 0 (Amino Acid Transport Systems, Neutral)
0 (CTNS protein, human)
0 (Codon, Nonsense)
0 (Gentamicins)
0 (RNA, Messenger)
0 (Recombinant Proteins)
48TCX9A1VT (Cystine)
A08F5XTI6G (antibiotic G 418)
تواريخ الأحداث: Date Created: 20181111 Date Completed: 20200505 Latest Revision: 20200505
رمز التحديث: 20231215
DOI: 10.1007/s00467-018-4094-0
PMID: 30413946
قاعدة البيانات: MEDLINE
الوصف
تدمد:1432-198X
DOI:10.1007/s00467-018-4094-0