Functional consequences of TCF4 missense substitutions associated with Pitt-Hopkins syndrome, mild intellectual disability, and schizophrenia
| Autor: | Jürgen Tuvikene, Kaisa Roots, Tõnis Timmusk, Alex Sirp, Kaja Nurm, Mari Sepp |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | The Journal of Biological Chemistry Journal of Biological Chemistry UnpayWall ORCID Microsoft Academic Graph PubMed Central |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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