دورية أكاديمية
Antisense Oligonucleotide Rescue of Deep-Intronic Variants Activating Pseudoexons in the 6-Pyruvoyl-Tetrahydropterin Synthase Gene.
العنوان: | Antisense Oligonucleotide Rescue of Deep-Intronic Variants Activating Pseudoexons in the 6-Pyruvoyl-Tetrahydropterin Synthase Gene. |
---|---|
المؤلفون: | Martínez-Pizarro A; Centro de Biología Molecular Severo Ochoa UAM-CSIC, Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), CIBERER, IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain., Leal F; Centro de Biología Molecular Severo Ochoa UAM-CSIC, Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), CIBERER, IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain., Holm LL; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Doktor TK; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Petersen USS; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Bueno M; Congenital Metabolic Diseases Unit, Hospital Virgen del Rocio, Sevilla, Spain., Thöny B; Division of Metabolism, University Children's Hospital Zürich, Zürich, Switzerland., Pérez B; Centro de Biología Molecular Severo Ochoa UAM-CSIC, Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), CIBERER, IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain., Andresen BS; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Desviat LR; Centro de Biología Molecular Severo Ochoa UAM-CSIC, Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), CIBERER, IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain. |
المصدر: | Nucleic acid therapeutics [Nucleic Acid Ther] 2022 Oct; Vol. 32 (5), pp. 378-390. Date of Electronic Publication: 2022 Jul 12. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101562758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-3345 (Electronic) Linking ISSN: 21593337 NLM ISO Abbreviation: Nucleic Acid Ther Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: New Rochelle, N.Y. : Mary Ann Liebert, Inc. |
مواضيع طبية MeSH: | RNA Splice Sites*/genetics , Oligonucleotides, Antisense*/genetics , Oligonucleotides, Antisense*/therapeutic use, Humans ; Phosphorus-Oxygen Lyases/genetics ; Exons/genetics ; Introns/genetics ; RNA Splicing/genetics ; Mutation ; Oligonucleotides |
مستخلص: | We report two new 6-pyruvoyl-tetrahydropterin synthase splicing variants identified through genomic sequencing and transcript analysis in a patient with tetrahydrobiopterin deficiency, presenting with hyperphenylalaninemia and monoamine neurotransmitter deficiency. Variant c.243 + 3A>G causes exon 4 skipping. The deep-intronic c.164-672C>T variant creates a potential 5' splice site that leads to the inclusion of four overlapping pseudoexons, corresponding to exonizations of an antisense short interspersed nuclear element AluSq repeat sequence. Two of the identified pseudoexons have been reported previously, activated by different deep-intronic variants, and were also detected at residual levels in control cells. Interestingly, the predominant pseudoexon is nearly identical to a disease causing activated pseudoexon in the F8 gene, with the same 3' and 5' splice sites. Splice switching antisense oligonucleotides (SSOs) were designed to hybridize with splice sites and/or predicted binding sites for regulatory splice factors. Different SSOs corrected the aberrant pseudoexon inclusion, both in minigenes and in fibroblasts from patients carrying the new variant c.164-672C>T or the previously described c.164-716A>T. With SSO treatment PTPS protein was recovered, illustrating the therapeutic potential of the approach, for patients with different pseudoexon activating variants in the region. In addition, the natural presence of pseudoexons in the wild type context suggests the possibility of applying the antisense strategy in patients with hypomorphic PTS variants with the purpose of upregulating their expression to increase overall protein and activity. |
References: | Trends Biochem Sci. 2008 Aug;33(8):385-93. (PMID: 18621535) Hum Mutat. 2022 Feb;43(2):253-265. (PMID: 34923709) Am J Hum Genet. 2018 Feb 1;102(2):199-206. (PMID: 29357978) J Mol Med (Berl). 2017 Mar;95(3):299-309. (PMID: 27837218) Nat Rev Genet. 2016 Jan;17(1):19-32. (PMID: 26593421) Mol Cell. 2004 Apr 23;14(2):221-31. (PMID: 15099521) EMBO Mol Med. 2021 Apr 9;13(4):e13243. (PMID: 33821570) Pathology. 2019 Apr;51(3):274-280. (PMID: 30853107) Eur J Pediatr. 1987 May;146(3):228-32. (PMID: 3297709) PLoS Comput Biol. 2013;9(8):e1003118. (PMID: 23950696) Mol Ther Methods Clin Dev. 2020 Sep 16;19:174-185. (PMID: 33209960) Mol Ther Nucleic Acids. 2020 Sep 4;21:412-427. (PMID: 32653833) Mol Cell. 2019 Sep 5;75(5):967-981.e9. (PMID: 31300274) Hum Mutat. 2011 Sep;32(9):1019-27. (PMID: 21542064) Genome Biol. 2007;8(6):R127. (PMID: 17594509) Nat Methods. 2016 Jun;13(6):508-14. (PMID: 27018577) J Comput Biol. 2004;11(2-3):377-94. (PMID: 15285897) FEBS J. 2010 Feb;277(4):841-55. (PMID: 20082636) Hum Mutat. 2022 Feb;43(2):103-127. (PMID: 34837434) Nat Rev Drug Discov. 2020 Mar;19(3):151-153. (PMID: 32127676) Science. 2021 Nov 05;374(6568):672. (PMID: 34735255) Gene Ther. 2004 Sep;11(18):1391-8. (PMID: 15229633) N Engl J Med. 2019 Oct 24;381(17):1644-1652. (PMID: 31597037) Sci Transl Med. 2020 Aug 26;12(558):. (PMID: 32848094) Nat Med. 2019 Jun;25(6):911-919. (PMID: 31160820) Lancet Neurol. 2018 Feb;17(2):111-112. (PMID: 29229374) Nat Genet. 2017 Jun;49(6):848-855. (PMID: 28416821) Haemophilia. 2020 Sep;26(5):847-854. (PMID: 32812322) J Biol Chem. 2021 Jan-Jun;296:100416. (PMID: 33600796) Am J Hum Genet. 2019 May 2;104(5):1007. (PMID: 31051109) Mol Cell. 2016 Feb 18;61(4):507-519. (PMID: 26876937) J Inherit Metab Dis. 2010 Aug;33(4):397-403. (PMID: 20577904) Nucleic Acids Res. 2003 Jul 1;31(13):3568-71. (PMID: 12824367) Hum Mutat. 1997;10(1):25-35. (PMID: 9222757) Sci Transl Med. 2017 Apr 19;9(386):. (PMID: 28424332) Nucleic Acid Ther. 2022 Apr;32(2):95-100. (PMID: 34520268) Nat Commun. 2020 Jul 9;11(1):3501. (PMID: 32647108) RNA Biol. 2021 Mar;18(3):382-390. (PMID: 32865117) Hum Mol Genet. 1995 Apr;4(4):675-9. (PMID: 7633417) Biochem J. 2011 Sep 15;438(3):397-414. (PMID: 21867484) Mol Genet Metab. 2021 Jun;133(2):123-136. (PMID: 33903016) Mol Genet Metab. 2020 Dec;131(4):380-389. (PMID: 33234470) Mol Cell Biol. 2004 Dec;24(24):10505-14. (PMID: 15572659) Hum Mutat. 1999;13(2):170. (PMID: 10094556) Hum Genet. 2010 Feb;127(2):135-54. (PMID: 19823873) Nucleic Acid Ther. 2014 Feb;24(1):48-56. (PMID: 24506780) PLoS Genet. 2018 Apr 23;14(4):e1007360. (PMID: 29684050) Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) Am J Hum Genet. 2021 Apr 1;108(4):696-708. (PMID: 33743207) Nucleic Acids Res. 2014 Jul;42(Web Server issue):W361-7. (PMID: 24829458) Nucleic Acids Res. 2009 May;37(9):e67. (PMID: 19339519) Hum Genet. 1998 Dec;103(6):686-93. (PMID: 9921904) Hum Genet. 2017 Sep;136(9):1093-1111. (PMID: 28497172) Genet Med. 2019 Aug;21(8):1751-1760. (PMID: 30643219) Mol Genet Metab. 2016 Nov;119(3):258-269. (PMID: 27595546) Adv Drug Deliv Rev. 2021 Nov;178:113834. (PMID: 34492233) Nat Genet. 2004 Oct;36(10):1073-8. (PMID: 15448691) Am J Hum Genet. 2018 Apr 5;102(4):517-527. (PMID: 29526278) Nucleic Acids Res. 2015 May 19;43(9):4627-39. (PMID: 25878036) Hum Mutat. 2010 Apr;31(4):437-44. (PMID: 20120036) Methods Mol Biol. 2016;1418:335-51. (PMID: 27008022) Cell Metab. 2018 Apr 3;27(4):714-739. (PMID: 29617640) J Biol Chem. 1995 Dec 8;270(49):29498-506. (PMID: 7493990) Clin Sci (Lond). 2017 Mar 1;131(5):355-368. (PMID: 28202748) Clin Chem. 2001 Mar;47(3):477-85. (PMID: 11238300) Front Genet. 2022 Jan 24;12:806946. (PMID: 35140743) Mol Ther. 2009 Mar;17(3):548-53. (PMID: 18813282) Hum Mutat. 2001;18(1):83. (PMID: 11438997) Nat Commun. 2017 Jun 12;8:15824. (PMID: 28604674) Hum Mutat. 2009 May;30(5):823-31. (PMID: 19280650) |
فهرسة مساهمة: | Keywords: antisense oligonucleotides; pseudoexons; splicing; tetrahydrobiopterin |
المشرفين على المادة: | EC 4.6.10 (6-pyruvoyltetrahydropterin synthase) 0 (RNA Splice Sites) 0 (Oligonucleotides, Antisense) EC 4.6.- (Phosphorus-Oxygen Lyases) 0 (Oligonucleotides) |
تواريخ الأحداث: | Date Created: 20220714 Date Completed: 20221025 Latest Revision: 20221104 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC9595628 |
DOI: | 10.1089/nat.2021.0066 |
PMID: | 35833796 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2159-3345 |
---|---|
DOI: | 10.1089/nat.2021.0066 |