Abstract
Mucopolysaccharidosis I (MPS I) is a genetic disorder caused by mutations on α-L-iduronidase (IDUA) gene, leading to low or null enzyme activity. As nonsense mutations are present in about two thirds of the patients, stop codon read through (SCRT) is a potential alternative to achieve enhanced enzyme activity. This mechanism suppresses premature stop codon mutations allowing the protein to be fully translated. Chloramphenicol is a peptidyl transferase inhibitor able to induce readthrough and is efficient in cross the blood brain barrier. In this work, fibroblasts from MPS I patients (p.W402X/p.W402X; p.R89W/p.W402X and p.Q70X/c.1739-1g>t) were treated with chloramphenicol, which resulted in 100-fold increase on IDUA activity on compound heterozygous fibroblasts. cDNA sequencing showed that only the alleles without the nonsense mutation were being amplified, even after treatment, leading us to suggest that the nonsense alleles were targeted to nonsense-mediated mRNA decay and that chloramphenicol acts through a mechanism other than SCRT.
Keywords: Alpha-l-iduronidase, Chloramphenicol, Mucopolysaccharidosis I, Nonsense Mediated RNA Decay, premature stop codon mutations, stop codon read through
Current Pharmaceutical Biotechnology
Title:Chloramphenicol Enhances IDUA Activity on Fibroblasts from Mucopolysaccharidosis I Patients
Volume: 14 Issue: 2
Author(s): Fabiana Quoos Mayer, Osvaldo Alfonso Artigalas, Valeska Lizzi Lagranha, Guilherme Baldo, Ida Vanessa Schwartz, Ursula Matte and Roberto Giugliani
Affiliation:
Keywords: Alpha-l-iduronidase, Chloramphenicol, Mucopolysaccharidosis I, Nonsense Mediated RNA Decay, premature stop codon mutations, stop codon read through
Abstract: Mucopolysaccharidosis I (MPS I) is a genetic disorder caused by mutations on α-L-iduronidase (IDUA) gene, leading to low or null enzyme activity. As nonsense mutations are present in about two thirds of the patients, stop codon read through (SCRT) is a potential alternative to achieve enhanced enzyme activity. This mechanism suppresses premature stop codon mutations allowing the protein to be fully translated. Chloramphenicol is a peptidyl transferase inhibitor able to induce readthrough and is efficient in cross the blood brain barrier. In this work, fibroblasts from MPS I patients (p.W402X/p.W402X; p.R89W/p.W402X and p.Q70X/c.1739-1g>t) were treated with chloramphenicol, which resulted in 100-fold increase on IDUA activity on compound heterozygous fibroblasts. cDNA sequencing showed that only the alleles without the nonsense mutation were being amplified, even after treatment, leading us to suggest that the nonsense alleles were targeted to nonsense-mediated mRNA decay and that chloramphenicol acts through a mechanism other than SCRT.
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Quoos Mayer Fabiana, Alfonso Artigalas Osvaldo, Lizzi Lagranha Valeska, Baldo Guilherme, Vanessa Schwartz Ida, Matte Ursula and Giugliani Roberto, Chloramphenicol Enhances IDUA Activity on Fibroblasts from Mucopolysaccharidosis I Patients, Current Pharmaceutical Biotechnology 2013; 14 (2) . https://dx.doi.org/10.2174/1389201011314020009
DOI https://dx.doi.org/10.2174/1389201011314020009 |
Print ISSN 1389-2010 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4316 |
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