Abstract
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.
Highlights
Transcription factor 4 (TCF4) is vital for normal development of the central nervous system, and the mutations within the TCF4 gene have been linked to several neurodevelopmental diseases such as Pitt-Hopkins syndrome (PTHS), mild-to-moderate intellectual disability (MMID), and schizophrenia (SCZ) [1]
Several missense variations and mutations across the TCF4 coding sequence have been identified in MMID, SCZ, RTTlike syndrome, and PTHS patients
All but one of the schizophrenia-associated missense variations have been identified in a single patient and no controls, the variation A315V has been found in 14 patients and 10 controls
Summary
Transcription factor 4 (TCF4) is vital for normal development of the central nervous system, and the mutations within the TCF4 gene have been linked to several neurodevelopmental diseases such as Pitt-Hopkins syndrome (PTHS), mild-to-moderate intellectual disability (MMID), and schizophrenia (SCZ) [1]. Mutant TCF4 proteins display changes in DNA binding, dimerization, transcription activation, and intranuclear localization. Several novel disease-related missense variations and the mutations associated with SCZ, MMID, RTT-like syndrome, and PTHS have been identified in TCF4, the functional impact of these substitutions has not been studied.
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