Mutational, functional, and expression studies of the<i>TCF4</i>gene in Pitt-Hopkins syndrome

Pontual, Loïc de; Mathieu, Yves; Golzio, Christelle; Rio, Marlène; Malan, Valérie; Boddaert, Nathalie; Soufflet, Christine; Pïcard, Capucine; Durandy, Anne; Dobbie, Angus; Héron, Delphine; Isidor, Bertrand; Motté, Jacques; Newburry-Ecob, Ruth; Pasquier, Laurent; Tardieu, Marc; Viot, Géraldine; Jaubert, Françis; Münnich, Arnold; Colleaux, Laurence; Vekemans, Michel; Etchevers, Heather C.; Lyonnet, Stanislas; Amiel, Jeanne

doi:10.1002/humu.20935

Cited by 133 publications

(214 citation statements)

References 26 publications

(28 reference statements)

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“…Tcf4 expression is sustained particularly in areas of high neuronal plasticity such as the cerebral cortex, hippocampus and cerebellum [13,112]. Human TCF4 expression has been detected in the prosencephalon and the ventricular zone of the embryonic CNS [133], in the telencephalon at all stages of fetal development as well as in the adult forebrain (http://www.brainspan.org/). In summary, TCF4 is the only E-protein being expressed at all stages in the developing and adult mouse and human brain.…”

Section: Tcf4/tcf4 Expression In Brain Developmentmentioning

confidence: 99%

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Quednow

Brzózka

Rossner

2014

Cell. Mol. Life Sci.

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Schizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits. Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4). Haploinsufficiency of the TCF4 (formatting follows IUPAC nomenclature: TCF4 protein/protein function, Tcf4 rodent gene cDNA mRNA, TCF4 human gene cDNA mRNA) gene causes the Pitt-Hopkins syndrome-a neurodevelopmental disease characterized by severe mental retardation. Accordingly, Tcf4 null-mutant mice display developmental brain defects. TCF4-associated risk alleles are located in putative coding and non-coding regions of the gene. Hence, subtle changes at the level of gene expression might be relevant for the etiopathology of schizophrenia. Behavioural phenotypes obtained with a mouse model of slightly increased gene dosage and electrophysiological investigations with human risk-allele carriers revealed an overlapping spectrum of schizophrenia-relevant endophenotypes. Most prominently, early information processing and higher cognitive functions appear to be associated with TCF4 risk genotypes. Moreover, a recent human study unravelled gene × environment interactions between TCF4 risk alleles and smoking behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental, and, possibly, plasticity-related transcriptional programs in the CNS and changes of TCF4 expression also appear to affect brain networks important for information processing. Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis for identifying the underlying molecular mechanisms. AbstractSchizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits.Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4 behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental and possibly also plasticity related transcriptional programs in the CNS and changes of TCF4 expression appear to affect brain networks important for information processing.Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis to identify the und...

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Section: Tcf4/tcf4 Expression In Brain Developmentmentioning

confidence: 99%

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Quednow

Brzózka

Rossner

2014

Cell. Mol. Life Sci.

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“…All mutations that cause PTHS are thought to result in haploinsufficiency of TCF4, consistent with the disorder being inherited in an autosomal dominant manner [62,63,67]. The majority of PTHS-associated missense mutations appear to attenuate transcriptional activity in reporter-based assays of gene function and also may impair heterodimer formation with other bHLH transcription factors [36,37,63,68].…”

Section: Pitt-hopkins Syndrome and Intellectual Disabilitymentioning

confidence: 96%

“…Intriguingly, TCF4-B has also been found to be a transcriptional repressor in different cell types [33][34][35]. However, it has been demonstrated that this isoform can also activate transcription in vitro, and therefore its function is highly context-dependent [30,36,37].…”

Section: Introductionmentioning

confidence: 99%

Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability

Hill

Forrest

Martin‐Rendon

et al. 2014

Curr Behav Neurosci Rep

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Genome wide association studies (GWAS) have revolutionized the study of complex diseases and have uncovered common genetic variants associated with an increased risk for major psychiatric disorders. A recently published schizophrenia GWAS replicated earlier findings implicating common variants in Transcription factor 4 (TCF4) as susceptibility loci for schizophrenia. By contrast, loss of function TCF4 mutations, although rare, cause Pitt-Hopkins syndrome (PTHS); a disorder characterized by intellectual disability (ID), developmental delay and behavioral abnormalities. TCF4 mutations have also been described in individuals with ID and non-syndromic neurodevelopmental disorders. TCF4 is a member of the basic helix-loop-helix (bHLH) family of transcription factors that regulate gene expression at E-boxcontaining promoters and enhancers. Accordingly, TCF4 has an important role during brain development and can interact with a wide array of transcriptional regulators including some proneural factors. TCF4 may, therefore, participate in the transcriptional networks that regulate the maintenance and differentiation of distinct cell types during brain development. Here, we review the role of TCF4 variants in the context of several distinct brain disorders associated with impaired cognition.

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“…In this study, an interaction of TCF4 and MATH1, a proneural protein, on different neural progenitor populations was investigated and disrupted pontine nucleus development was found in TCF4 knock out mice. Second, several studies showed that TCF4 haploinsufficiency contributes to severe neurodevelopmental disorders such as the Pitt-Hopkins syndrome [1,4,9,33,40]. This autosomal dominant encephalopathy is characterized by severe mental retardation, microcephaly, disrupted motor development, and hyperventilation, as described above [25].…”

Section: Tcf4 and Cognitive Endophenotypes Of Schizophreniamentioning

confidence: 97%

Impact of TCF4 on the genetics of schizophrenia

Lennertz

Quednow

Benninghoff

et al. 2011

Eur Arch Psychiatry Clin Neurosci

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Mutations of the transcription factor 4 (TCF4) gene cause mental retardation with or without associated facial dysmorphisms and intermittent hyperventilation. Subsequently, a polymorphism of TCF4 was shown in a genome-wide association study to slightly increase the risk of schizophrenia. We have further analysed the impact of this TCF4 variant rs9960767 on early information processing and cognitive functions in schizophrenia patients. We have shown in a sample of 401 schizophrenia patients that TCF4 influences verbal memory in the Rey Auditory Verbal Learning Test. Contrary to expectations, carriers of the schizophrenia-associated allele showed better recognition, thus indicating that while TCF4 influences verbal memory, the TCF4-mediated schizophrenia risk is not determined by the influence of TCF4 on verbal memory. TCF4 does not impact on various other cognitive functions belonging to the domains of attention and executive functions. Moreover, in a pharmacogenetic approach, TCF4 does not modulate the improvement of positive or negative schizophrenia symptoms during treatment with antipsychotics. Finally, we have assessed a key electrophysiological endophenotype of schizophrenia, sensorimotor gating. As measured by prepulse inhibition, the schizophrenia risk allele C of TCF4 rs9960767 reduces sensorimotor gating. This indicates that TCF4 influences key mechanisms of information processing, which may contribute to the pathogenesis of schizophrenia.

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Mutational, functional, and expression studies of theTCF4gene in Pitt-Hopkins syndrome

Cited by 133 publications

References 26 publications

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability

Impact of TCF4 on the genetics of schizophrenia

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