Functional consequences of TCF4 missense substitutions associated with Pitt-Hopkins syndrome, mild intellectual disability, and schizophrenia
| العنوان: | Functional consequences of TCF4 missense substitutions associated with Pitt-Hopkins syndrome, mild intellectual disability, and schizophrenia |
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| المؤلفون: | Jürgen Tuvikene, Kaisa Roots, Tõnis Timmusk, Alex Sirp, Kaja Nurm, Mari Sepp |
| المصدر: | The Journal of Biological Chemistry Journal of Biological Chemistry UnpayWall ORCID Microsoft Academic Graph PubMed Central |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Transcription, Genetic, TCF4, Transcription factor 4, neurocognitive disorders, Pitt–Hopkins syndrome, medicine.disease_cause, Biochemistry, Rats, Sprague-Dawley, Transcription Factor 4, Intellectual disability, Missense mutation, Hyperventilation, Genetics, Mutation, Helix-Loop-Helix Motifs, TCF4, single-nucleotide polymorphism, transcription factor TCF4, SCZ, Schizophrenia, CE, conserved element, PGK, phosphoglycerine kinase, MMID, Mild-to-moderate intellectual disability, Research Article, Gene isoform, basic helix-loop-helix transcription factor, RTT-like, Rett-like syndrome, Mutation, Missense, autism, TK, thymidine kinase, Single-nucleotide polymorphism, NLS, Nuclear localization signal, Biology, PBST, PBS with Tween 20, bHLH, basic helix-loop-helix, PTHS, Pitt-Hopkins syndrome, Intellectual Disability, Pitt-Hopkins syndrome, medicine, Animals, Humans, Molecular Biology, Transcription factor, missense mutation, Facies, Cell Biology, AD, activation domain, medicine.disease, neuron, Rats, schizophrenia, HEK293 Cells, Amino Acid Substitution, ASCL1, achaete-scute homolog 1, BSA, bovine serum albumin |
| الوصف: | 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. |
| تدمد: | 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::571fb9a500003d0acbefc612aacd700eTest https://pubmed.ncbi.nlm.nih.gov/34748727Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....571fb9a500003d0acbefc612aacd700e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219258 |
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