Mutation-adapted U1 snRNA corrects a splicing error of the dopa decarboxylase gene
Journal
Human Molecular Genetics
Journal Volume
25
Journal Issue
23
Pages
5142-5147
Date Issued
2016
Author(s)
Abstract
Aromatic L-amino acid decarboxylase (AADC) deficiency is an inborn error of monoamine neurotransmitter synthesis, which results in dopamine, serotonin, epinephrine and norepinephrine deficiencies. The DDC gene founder mutation IVS6+4A > T is highly prevalent in Chinese patients with AADC deficiency. In this study, we designed several U1 snRNA vectors to adapt U1 snRNA binding sequences of the mutated DDC gene. We found that only the modified U1 snRNA (IVS-AAA) that completely matched both the intronic and exonic U1 binding sequences of the mutated DDC gene could correct splicing errors of either the mutated human DDC minigene or the mouse artificial splicing construct in vitro. We further injected an adeno-associated viral (AAV) vector to express IVS-AAA in the brain of a knock-in mouse model. This treatment was well tolerated and improved both the survival and brain dopamine and serotonin levels of mice with AADC deficiency. Therefore, mutation-adapted U1 snRNA gene therapy can be a promising method to treat genetic diseases caused by splicing errors, but the efficiency of such a treatment still needs improvements. ? The Author 2016. Published by Oxford University Press. All rights reserved.
SDGs
Other Subjects
adeno associated virus vector; aromatic levo amino acid decarboxylase; dopamine; serotonin; small nuclear RNA; agents interacting with transmitter, hormone or drug receptors; aromatic levo amino acid decarboxylase; small nuclear RNA; U1 small nuclear RNA; animal cell; animal experiment; animal model; Article; cell survival; controlled study; dopamine brain level; gene mutation; gene sequence; human; intron; mouse; nonhuman; priority journal; protein expression; RNA splicing; serotonin brain level; Amino Acid Metabolism, Inborn Errors; animal; deficiency; Dependoparvovirus; disease model; exon; gene targeting; gene therapy; genetics; mutation; RNA splicing; Amino Acid Metabolism, Inborn Errors; Animals; Aromatic-L-Amino-Acid Decarboxylases; Dependovirus; Disease Models, Animal; Dopa Decarboxylase; Exons; Gene Knock-In Techniques; Genetic Therapy; Humans; Introns; Mice; Mutation; Neurotransmitter Agents; RNA Splicing; RNA, Small Nuclear
Publisher
Oxford University Press
Type
journal article