ArticleEuropean journal of human genetics : EJHG2015
Functional correction by antisense therapy of a splicing mutation in the GALT gene.
Article in European journal of human genetics : EJHG, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 1 of them a synthesis that pooled it.
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Who cites it
8 citing papers in PubMed, 1 synthesis or guideline pooled it, 17 citations in OpenAlex.
- Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models.Journal of inherited metabolic disease · 2020Pooled it
- Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders.Bioengineering (Basel, Switzerland) · 2022Review
- Molecular analysis ofMolecular genetics and metabolism reports · 2020Article
- Classic galactosaemia in the Greek Cypriot population: An epidemiological and molecular study.Annals of human genetics · 2019Article
- Pilot study of classic galactosemia: Neurodevelopmental impact and other complications urge neonatal screening in Egypt.Journal of advanced research · 2018Article
- "Transcriptomics": molecular diagnosis of inborn errors of metabolism via RNA-sequencing.Journal of inherited metabolic disease · 2018Review
- Sweet and sour: an update on classic galactosemia.Journal of inherited metabolic disease · 2017Review
- Variants of uncertain significance in newborn screening disorders: implications for large-scale genomic sequencing.Genetics in medicine : official journal of the American College of Medical Genetics · 2017Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In recent years, antisense therapy has emerged as an increasingly important therapeutic approach to tackle several genetic disorders, including inborn errors of metabolism. Intronic mutations activating cryptic splice sites are particularly amenable to antisense therapy, as the canonical splice sites remain intact, thus retaining the potential for restoring constitutive splicing. Mutational analysis of Portuguese galactosemic patients revealed the intronic variation c.820+13A>G as the second most prevalent mutation, strongly suggesting its pathogenicity. The aim of this study was to functionally characterize this intronic variation, to elucidate its pathogenic molecular mechanism(s) and, ultimately, to correct it by antisense therapy. Minigene splicing assays in two distinct cell lines and patients' transcript analyses showed that the mutation activates a cryptic donor splice site, inducing an aberrant splicing of the GALT pre-mRNA, which in turn leads to a frameshift with inclusion of a premature stop codon (p.D274Gfs*17). Functional-structural studies of the recombinant wild-type and truncated GALT showed that the latter is devoid of enzymatic activity and prone to aggregation. Finally, two locked nucleic acid oligonucleotides, designed to specifically recognize the mutation, successfully restored the constitutive splicing, thus establishing a proof of concept for the application of antisense therapy as an alternative strategy for the clearly insufficient dietary treatment in classic galactosemia.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.