Title: Antisense oligonucleotides modulate dopa decarboxylase function in aromatic <scp>l</scp> -amino acid decarboxylase deficiency
Abstract: Human MutationVolume 39, Issue 12 p. 2072-2082 RESEARCH ARTICLE Antisense oligonucleotides modulate dopa decarboxylase function in aromatic l-amino acid decarboxylase deficiency Chi-Ren Tsai, Chi-Ren Tsai Institute of Molecular Biology, National Chung Hsing University, Taichung, 402 Taiwan Department of Pediatrics, Taichung Veterans General Hospital, Taichung, 407 TaiwanSearch for more papers by this authorHsiu-Fen Lee, Hsiu-Fen Lee Department of Pediatrics, Taichung Veterans General Hospital, Taichung, 407 Taiwan School of Medicine, Chung Shan Medical University, Taichung, 402 TaiwanSearch for more papers by this authorChing-Shiang Chi, Corresponding Author Ching-Shiang Chi [email protected] orcid.org/0000-0003-0766-809X School of Medicine, Chung Shan Medical University, Taichung, 402 Taiwan Department of Pediatrics, Tung's Taichung Metroharbor Hospital, Taichung, 435 Taiwan Correspondence Dr. Ching-Shiang Chi, Department of Pediatrics, Tungs' Taichung Metroharbor Hospital, 699, Taiwan Boulevard Sec. 8, Wuchi, Taichung 435, Taiwan. Email: [email protected] Dr. Ming-Te Yang, Institute of Molecular Biology, National Chung Hsing University, 250 Kuo Kuang Rd., Taichung 402, Taiwan. Email: [email protected] for more papers by this authorMing-Te Yang, Corresponding Author Ming-Te Yang [email protected] Institute of Molecular Biology, National Chung Hsing University, Taichung, 402 Taiwan Correspondence Dr. Ching-Shiang Chi, Department of Pediatrics, Tungs' Taichung Metroharbor Hospital, 699, Taiwan Boulevard Sec. 8, Wuchi, Taichung 435, Taiwan. Email: [email protected] Dr. Ming-Te Yang, Institute of Molecular Biology, National Chung Hsing University, 250 Kuo Kuang Rd., Taichung 402, Taiwan. Email: [email protected] for more papers by this authorChia-Chi Hsu, Chia-Chi Hsu Department of Pediatrics, Taichung Veterans General Hospital, Taichung, 407 Taiwan Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, 112 TaiwanSearch for more papers by this author Chi-Ren Tsai, Chi-Ren Tsai Institute of Molecular Biology, National Chung Hsing University, Taichung, 402 Taiwan Department of Pediatrics, Taichung Veterans General Hospital, Taichung, 407 TaiwanSearch for more papers by this authorHsiu-Fen Lee, Hsiu-Fen Lee Department of Pediatrics, Taichung Veterans General Hospital, Taichung, 407 Taiwan School of Medicine, Chung Shan Medical University, Taichung, 402 TaiwanSearch for more papers by this authorChing-Shiang Chi, Corresponding Author Ching-Shiang Chi [email protected] orcid.org/0000-0003-0766-809X School of Medicine, Chung Shan Medical University, Taichung, 402 Taiwan Department of Pediatrics, Tung's Taichung Metroharbor Hospital, Taichung, 435 Taiwan Correspondence Dr. Ching-Shiang Chi, Department of Pediatrics, Tungs' Taichung Metroharbor Hospital, 699, Taiwan Boulevard Sec. 8, Wuchi, Taichung 435, Taiwan. Email: [email protected] Dr. Ming-Te Yang, Institute of Molecular Biology, National Chung Hsing University, 250 Kuo Kuang Rd., Taichung 402, Taiwan. Email: [email protected] for more papers by this authorMing-Te Yang, Corresponding Author Ming-Te Yang [email protected] Institute of Molecular Biology, National Chung Hsing University, Taichung, 402 Taiwan Correspondence Dr. Ching-Shiang Chi, Department of Pediatrics, Tungs' Taichung Metroharbor Hospital, 699, Taiwan Boulevard Sec. 8, Wuchi, Taichung 435, Taiwan. Email: [email protected] Dr. Ming-Te Yang, Institute of Molecular Biology, National Chung Hsing University, 250 Kuo Kuang Rd., Taichung 402, Taiwan. Email: [email protected] for more papers by this authorChia-Chi Hsu, Chia-Chi Hsu Department of Pediatrics, Taichung Veterans General Hospital, Taichung, 407 Taiwan Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, 112 TaiwanSearch for more papers by this author First published: 27 September 2018 https://doi.org/10.1002/humu.23659Citations: 4 Funding information: This work was supported by the Taichung Veterans General Hospital (TCVGH-1036501A to C.R.T.). Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Aromatic l-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. CONFLICTS OF INTEREST The authors declare no conflict of interest. Citing Literature Supporting Information Filename Description humu23659-sup-0001-SuppMat.pdf3.2 MB Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume39, Issue12December 2018Pages 2072-2082 RelatedInformation