دورية أكاديمية
أعرض في EDS

Antisense Oligonucleotide Rescue of Deep-Intronic Variants Activating Pseudoexons in the 6-Pyruvoyl-Tetrahydropterin Synthase Gene.

التفاصيل البيبلوغرافية
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.
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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
الوصف
تدمد:2159-3345
DOI:10.1089/nat.2021.0066