دورية أكاديمية
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Functional consequences of TCF4 missense substitutions associated with Pitt-Hopkins syndrome, mild intellectual disability, and schizophrenia.

التفاصيل البيبلوغرافية
العنوان: Functional consequences of TCF4 missense substitutions associated with Pitt-Hopkins syndrome, mild intellectual disability, and schizophrenia.
المؤلفون: Sirp A; Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia., Roots K; Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia., Nurm K; Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia., Tuvikene J; Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia; Protobios LLC, Tallinn, Estonia., Sepp M; Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia. Electronic address: m.sepp@zmbh.uni-heidelberg.de., Timmusk T; Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia; Protobios LLC, Tallinn, Estonia. Electronic address: tonis.timmusk@taltech.ee.
المصدر: The Journal of biological chemistry [J Biol Chem] 2021 Dec; Vol. 297 (6), pp. 101381. Date of Electronic Publication: 2021 Nov 06.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
مواضيع طبية MeSH: Facies* , Hyperventilation*/genetics , Hyperventilation*/metabolism , Intellectual Disability*/genetics , Intellectual Disability*/metabolism , Mutation, Missense* , Schizophrenia*/genetics , Schizophrenia*/metabolism , Transcription Factor 4*/chemistry , Transcription Factor 4*/genetics , Transcription Factor 4*/metabolism , Transcription, Genetic*, Amino Acid Substitution ; Animals ; HEK293 Cells ; Helix-Loop-Helix Motifs ; Humans ; Rats ; Rats, Sprague-Dawley
مستخلص: Transcription factor 4 (TCF4) is a basic helix-loop-helix transcription factor essential for neurocognitive development. The aberrations in TCF4 are associated with neurodevelopmental disorders including schizophrenia, intellectual disability, and Pitt-Hopkins syndrome, an autism-spectrum disorder characterized by developmental delay. Several disease-associated missense mutations in TCF4 have been shown to interfere with TCF4 function, but for many mutations, the impact remains undefined. Here, we tested the effects of 12 functionally uncharacterized disease-associated missense mutations and variations in TCF4 using transient expression in mammalian cells, confocal imaging, in vitro DNA-binding assays, and reporter assays. We show that Pitt-Hopkins syndrome-associated missense mutations within the basic helix-loop-helix domain of TCF4 and a Rett-like syndrome-associated mutation in a transcription activation domain result in altered DNA-binding and transcriptional activity of the protein. Some of the missense variations found in schizophrenia patients slightly increase TCF4 transcriptional activity, whereas no effects were detected for missense mutations linked to mild intellectual disability. We in addition find that the outcomes of several disease-related mutations are affected by cell type, TCF4 isoform, and dimerization partner, suggesting that the effects of TCF4 mutations are context-dependent. Together with previous work, this study provides a basis for the interpretation of the functional consequences of TCF4 missense variants.
Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of the article.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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فهرسة مساهمة: Keywords: Pitt-Hopkins syndrome; autism; basic helix-loop-helix transcription factor; intellectual disability; missense mutation; neurocognitive disorders; neuron; schizophrenia; single-nucleotide polymorphism; transcription factor TCF4
المشرفين على المادة: 0 (TCF4 protein, human)
0 (Tcf4 protein, rat)
0 (Transcription Factor 4)
SCR Disease Name: Pitt-Hopkins syndrome
تواريخ الأحداث: Date Created: 20211108 Date Completed: 20220126 Latest Revision: 20230921
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8648840
DOI: 10.1016/j.jbc.2021.101381
PMID: 34748727
قاعدة البيانات: MEDLINE
الوصف
تدمد:1083-351X
DOI:10.1016/j.jbc.2021.101381