Antisense oligonucleotides modulate dopa decarboxylase function in aromatic l‐amino acid decarboxylase deficiency. Issue 12 (12th October 2018)

• Record Type: Journal Article
• Authors: Tsai, Chi‐Ren; Lee, Hsiu‐Fen; Chi, Ching‐Shiang; Yang, Ming‐Te; Hsu, Chia‐Chi
• Is Part Of: Human mutation. Volume 39:Issue 12(2018)
• Page Start: 2072
• Page End: 2082
• Publication Date: 2018-10-12
• Subjects: Aromatic l‐amino acid decarboxylase deficiency (AADCD) -- antisense oligonucleotide (ASO) -- dopa decarboxylase (DDC); Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23659
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Aromaticl ‐amino acid decarboxylase deficiency (AADCD), attributed to mutations in the dopa decarboxylase ( DDC ) gene, is a rare neurometabolic disease resulting from a defect in the biosynthesis of dopamine and serotonin. The DDC c.714+4A>T mutation is the most prevalent mutation among patients with AADCD, and is also a founder mutation among Taiwanese patients. In this study, the molecular consequences and function of this mutation were examined in AADCD patient‐derived lymphoblastoid cells. We identified novel DDC mRNA isoforms spliced with a new exon (exon 6a) in normal and c.714+4A>T lymphoblastoid cells. In addition, we identified the SR proteins (SRSF9 and SRSF6), as well as cis ‐elements involved in modulating the splicing of this mutated transcript. Notably, we demonstrated that antisense oligonucleotides (ASOs) were able to restore the normal mRNA splicing and increase the level of DDC protein, as well as its downstream product serotonin, in lymphoblastoid cells derived from the patient with AADCD, suggesting that these ASOs might represent a feasible alternative strategy for gene therapy of AADCD in patients with the common c.714+4A>T mutation. Abstract : Antisense oligonucleotides (ASOs) were able to modulate the mRNA splicing errors and increase the level of DDC protein, as well as its downstream product serotonin, in lymphoblastoid cells derived from AADCD patient bearing with founder splicing mutation.