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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Article Synopsis
- Mucopolysaccharidosis type I (MPS I) is a rare condition caused by a deficiency in the enzyme α-L-iduronidase (IDUA), leading to the buildup of glycosaminoglycans and various health issues.
- Current treatments like stem cell transplants and enzyme replacement often fall short in addressing all patient symptoms.
- In a study with MPS I mice, administering a specific viral vector (RGX-111) at a minimal dose of 10 vector genomes showed significant metabolic improvement and reduced severe symptoms, suggesting a promising approach for human therapy.
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