Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A second de novo protein-truncating variant in TCF4 in an ASD proband from the Autism Sequencing Consortium was reported in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified TCF4 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Two additional de novo loss-of-function variants and three potentially damaging de novo missense variants in the TCF4 gene were reported in ASD probands from the MSSNG cohort and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified TCF4 as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).
Molecular Function
This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor that binds to the immunoglobulin enchancer Mu-E5/KE5-motif and is involved in the initiation of neuronal differentiation. Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954], a syndrome characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Development, cognition, and behaviour in Pitt-Hopkins syndrome.
Tcf4 haploinsufficient mice have deficits in social interaction, ultrasonic vocalization, prepulse inhibition, and spatial and associative learning and memory and have Incresed general locomotor activity . Tcf4(+/) mice also show enhanced long-term potentiation in the CA1 area of the hippocampus. Hdac2 isoform-selective knockdown or adminstration of Hdac inhibitors can rescue memory deficits in Tcf4(+/) mice.
References
Type
Title
Author, Year
Primary
Tcf4 Regulates Synaptic Plasticity, DNA Methylation, and Memory Function.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The C-terminus DNA-binding domain of transcription factor 4 (Tcf4 or E2-2) was replaced with a neomycin cassette.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6J and 129S1/SvImJ
Genetic Background: C57BL/6J*129S1/SvImJ
ES Cell Line: 129P2/OlaHsd
Mutant ES Cell Line: Not specified
Model Source: Jax Lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice harboring a homozygous deletion of the C-terminus DNA-binding domain of transcription factor 4 (Tcf4 or E2-2) which was replaced with a neomycin cassette.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6J and 129S1/SvImJ
Genetic Background: C57BL/6J*129S1/SvImJ
ES Cell Line: 129P2/OlaHsd
Mutant ES Cell Line: Not specified
Model Source: Jax Lab
Description: Increased general locomotor activity in tcf4 hets relative to wildtype controls
Exp Paradigm: Open field test: tcf4 hets show higher activity without affecting the overal time spent in the center of the field; elevated plus maze test: tcf4 hets show an increase in overall arm entrances without spending a significantly increased amount of time in the open arms- elevated plus maze test
Description: Tcf hets have weaker hindlimb, but not forelimb, grip strength relative to wildtype controls
Exp Paradigm: Grip strength test measures grip strength by using the grip strength meter
Description: Tcf4 hets have asymmetry in the motor control and imbalance that favors their left side
Exp Paradigm: Dynamic weight bearing: tcf4 hets place more weight on their front left paw than their right; catwalk: tcf4 hets favor their front left paw while walking-dynamic weight bearing
Description: Increased general locomotor activity in tcf4 hets relative to wildtype controls
Exp Paradigm: Open field test: tcf4 hets show higher activity without affecting the overal time spent in the center of the field; elevated plus maze test: tcf4 hets show an increase in overall arm entrances without spending a significantly increased amount of time in the open arms-open field test
Description: Tcf4 hets have asymmetry in the motor control and imbalance that favors their left side
Exp Paradigm: Dynamic weight bearing: tcf4 hets place more weight on their front left paw than their right; catwalk: tcf4 hets favor their front left paw while walking- catwalk
Description: Tcf4 het mice show an increase in the total number of late born neurons (e14) but a decrease in the total number of early born neurons (e12) at p4, p7 and p15, compared with controls, indicating a decrease in the generation of upper cortical layer neurons.
Exp Paradigm: Early and late born neurons were labelled with idu and cidu respectively at e12 and e14. cerebral cortex.
Description: Fewer phox2b immunoreactive neurons along the rostrocaudal extent of the retrotrapezoid nucleus (rtn) and parafacial lateral (pfl) regions from tcf4tr/+ mice compared to control tissue; 70% fewer phox2b labeled neurons in the pfl region; rtn also showed a 21% loss of phox2b-immunoreactivity
Description: Cell type specific targeting of rtn projections to the pre-bötc was disrupted in tcf4tr/+ mice; phox2b parafacial neurons in phox2bcre::ai14::tcf4tr/+ animals project almost exclusively to sst-negative pre-bötc neurons, as opposed to sst-positive in control mice
Dendritic architecture: dendritic tree complexity2
Decreased
Description: Tcf4 het mice show apical dendrites with scarce ramification and sparse basal dendrites compared with controls.
Exp Paradigm: Scattered in utero electroporation was performed using gfp at e14 and dendritic morphology of the posterior neocortex was examined at p15.
Description: Tcf4 het mice show increased number of late born cldu labeled neurons remaining in the deep layers of the telencephalic wall en route to the cortical plate compared with controls, indicating a decrease in the migration of upper cortical layer neurons.
Exp Paradigm: Early and late born neurons were labelled with idu and cidu respectively at e12 and e14. cerebral cortex.
Description: Tcf4 het mice show shorter basal dendrites and longer apical dendrites compared with controls.
Exp Paradigm: Scattered in utero electroporation was performed using gfp at e14 and dendritic morphology of the posterior neocortex was examined at p15.
Description: Glutamatergic phox2b+ parafacial neurons are selectively disrupted by loss of tcf4; the proportion of slc17a6+ and phox2b+ parafacial neurons decreased from 61 to 47%, while the proportion of slc17a6+ and phox2b-negative neurons remained similar in tissue from control and tcf4tr/+ mice, respectively
Description: Tcf4 het mice show accumulation of e14 injected gfp primarily in the deep cortical layers of cux1 negative neurons whereas wildtype controls show accumulation of e14 injected gfp primarily in the upper cortical layers of cux1 positive neurons, indicating reduced neuronal migration in mutants.
Exp Paradigm: Gfp was injected in utero into e14 embryos. cerebral cortex.
Neuronal activation following behavioral stimulation: c-fos levels1
Increased
Description: Tcf4 hets have increased expression of fos (a transcription factor associated with memory formation in hippocampus) and tet2 (a 5-methyl cytosine hydroxylase) in the hippocampal ca1 tissue after training
Exp Paradigm: Rna sequencing: hippocampal ca1 collected after fear conditioning training
Description: Decreased sensorimotor gating in tcf4 hets relative to wildtype controls
Exp Paradigm: Prepulse inhibition: a 4 khz prepulse is presented 0, 4, 8, and 16 db above a 65 db background white noise before the pulse (120 db)
Description: Tcf4tr/+ mice show waxing and waning of minute ventilation resulting in unstable breathing evidenced by a large increase in minute ventilation coefficient of variation; ~75% of adult tcf4tr/+ mice exhibited a diminished occurrence of spontaneous sighs in conjunction with increased duration of post-sigh apnea; tcf4tr/+ mice show a diminished capacity to increase minute ventilation in response to 5 and 7% co2; normal ventilatory response to hypoxia
Exp Paradigm: room air; graded increases in CO2
Description: Tcf4 het pups (p3-p5) have reduced usv occurrence and weaker calls (p3) when they are removed from the nest
Exp Paradigm: The strength of calls is measured at the maximum pressure (in decibels) between 20 and 100 khz during the 5 min test window
Description: Tcf4 het pups (p3) have reduced usv occurrence and weaker calls when they are under stress
Exp Paradigm: Ultrasonic distress calls are elicited by lifting and holding the pup by hand for 30 sec after the 5 min usv detection period
Description: Tcf4 hets display decreased spatial memory examined by morris water maze test and object-place recognition test
Exp Paradigm: Morris water maze test: time in target quadrant or platform crossings; object-place recognition test-morris water maze test
Cued or contextual fear conditioning: trace fear conditioning1
Decreased
Description: Decreased memory of cue in trace fear conditioning test relative to wildtype controls
Exp Paradigm: Fear conditioning test: cued memory is assessed 1 day or 11 days after training
Description: Tcf4 hets display decreased spatial memory examined by morris water maze test and object-place recognition test
Exp Paradigm: Morris water maze test: time in target quadrant or platform crossings; object-place recognition test- object-place recognition test
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Decreased memory of cue in fear conditioning test with normal learning ability relative to wildtype controls
Exp Paradigm: Fear conditioning test: a training protocol is used to pair three white noise tones (cs) with a foot shock (us) presented 15 sec after the end of the cs; the memory is tested 24 hr after training sessions
Description: Tcf4 hets display impaired spatial learning with normal willingness and swim ability
Exp Paradigm: Morris water maze test: latency to platform; object-place recognition test-morris water maze test
Cued or contextual fear conditioning: memory of context1
Decreased
Description: Decreased memory of context in fear conditioning test with normal learning ability relative to wildtype controls
Exp Paradigm: Fear conditioning test: a training protocol is used to pair three white noise tones (cs) with a foot shock (us) presented 15 sec after the end of the cs; the memory is tested 24 hr after training sessions
Description: Tcf4 hets display impaired spatial learning with normal willingness and swim ability
Exp Paradigm: Morris water maze test: latency to platform; object-place recognition test- object-place recognition test
Description: Parafacial astrocytes in tcf4tr/+ mice crossed with an astrocyte specific inducible reporter (gfapcre/ert2) did not express tcf4 transcript
Description: Tcf4 het mice show upregulated genes primarily in the ventricular and sub ventricular zone enriched in genes involved in the proliferation of neurons, cell fate determination and cell migration and downregulated genes in the cortical plate and intermediate zone enriched in genes involved in schizophrenia, neurotransmitter release and sodium transporter activity, compared with controls, indicating a neocortical shift toward immature neurons (geo#: gse79663)
Exp Paradigm: Dorsal telencephalon
Description: Detectable levels of scn10a transcript in phox2b+ neurons from adult tcf4tr/+ mice but not age matched tcf4+/+ control animals
Exp Paradigm: FACS to obtain an enriched populations of TdT-positive cells from each genotype for subsequent targeted qPCR analysis of Scn10a transcript
Description: Tcf4 hets display reduced methylation across all gene bodies that is enriched with the upregulated differentially expressed genes; no change in the global methylation patterns across promoter regions
Exp Paradigm: Cpg methylomics analysis
Description: Tcf4 null mice show almost no cux1 (layers 2,3,4 in the sensory cortices) positive neurons in the upper cortical layers in the visual and parietal cortices but retain some cux1 expression in the frontal and motor cortices; increase in superficial layer markers satb2 and brn2 in deeper cortical layers particularly in the occipital and frontal cortices , indicating a defect in migration resulting in aberrant cortical lamination; no change in layer 5 marker ctip2; and reduction in layer 6 marker tbr1 compared with controls. tcf4 null mice do not show a gradient effect of the reduction in tbr1-positive cells along the anteriorposterior axis of the neocortex.
Exp Paradigm: Posterior neocortex
Description: Tcf4 null mice show increased proliferation of early and mid neurogenesis stage neuronal precursors compared with controls.
Exp Paradigm: Cerebral cortex
Description: Tcf4 null mice show increase in ki67 and phospho-histone h3 positive neurons in the cerebral cortex at e12 and e14 compared with controls, indicating an increase in cell proliferation. tcf4 null mice show increase in tbr2 positive intermediate progenitor neurons in the ventricular and subventricular zones of the cerebral cortex compared with controls.
Exp Paradigm: Ventricular and subventricular zones of the cerebral cortex
Description: Tcf4 het mice show upregulated genes primarily in the ventricular and sub ventricular zone enriched in genes involved in the proliferation of neurons, cell fate determination and cell migration and downregulated genes in the cortical plate and intermediate zone enriched in genes involved in schizophrenia, neurotransmitter release and sodium transporter activity, compared with controls, indicating a neocortical shift toward immature neurons (geo#: gse79663)
Exp Paradigm: Dorsal telencephalon
