Correction of the Pathogenic Alternative Splicing, Caused by the CommonGNB3c.825C>T Allele, Using a Novel, Antisense Morpholino
| Autor: | Douglas H. Lester, Jonathan C. P. McGlinchey, Hemanth Tummala |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Morpholino Biology Biochemistry Cell Line Morpholinos 03 medical and health sciences Exon Drug Discovery Genetics Humans Genetic Predisposition to Disease splice Allele Molecular Biology Gene Alleles Alternative splicing Heterotrimeric GTP-Binding Proteins Molecular biology Alternative Splicing 030104 developmental biology RNA splicing Molecular Medicine RNA Splice Sites Essential Hypertension Oligoribonucleotides Antisense GNB3 |
| Zdroj: | Nucleic Acid Therapeutics. 26:257-265 |
| ISSN: | 2159-3345 2159-3337 |
| DOI: | 10.1089/nat.2015.0571 |
| Popis: | The very common GNB3 c.825CT polymorphism (rs5443) is present in approximately half of all human chromosomes. Significantly, the presence of the GNB3 825T allele has been strongly associated with predisposition to essential hypertension. Paradoxically the presence of the GNB3 825T allele, in exon 10, introduces a pathogenic alternative RNA splice site into the middle of exon 9. To attempt to correct this pathogenic aberrant splicing, we, therefore, bioinformatically designed, using a Gene Tools(®) algorithm, a GNB3-specific, antisense morpholino. It was hoped that this morpholino would behave in vitro as either a potential splice blocker and/or exon skipper, to both bind and inhibit/reduce the aberrant splicing of the GNB3 825T allele. On transfecting a human lymphoblast cell line homozygous for the 825T allele, with this antisense morpholino, we encouragingly observed both a significant reduction (from ∼58% to ∼5%) in the production of the aberrant smaller GNB3 transcript, and a subsequent increase in the normal GNB3 transcript (from ∼42% to ∼95%). Our results demonstrate the potential use of a GNB3-specific antisense morpholino, as a pharmacogenetic therapy for essential hypertension. |
| Databáze: | OpenAIRE |
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