Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome

Max Planck Institute for Molecular Genetics, Berlin, Germany.
American Journal of Medical Genetics Part A (Impact Factor: 2.05). 08/2008; 146A(16):2053-9. DOI: 10.1002/ajmg.a.32419
Source: PubMed

ABSTRACT We have characterized a de novo balanced translocation t(18;20)(q21.1;q11.2) in a female patient with mild to moderate mental retardation (MR) and minor facial anomalies. Breakpoint-mapping by fluorescence in situ hybridization indicated that on chromosome 18, the basic helix-loop-helix transcription factor TCF4 gene is disrupted by the breakpoint. TCF4 plays a role in cell fate determination and differentiation. Only recently, mutations in this gene have been shown to result in Pitt-Hopkins syndrome (PHS), defined by severe MR, epilepsy, mild growth retardation, microcephaly, daily bouts of hyperventilation starting in infancy, and distinctive facial features with deep-set eyes, broad nasal bridge, and wide mouth with widely spaced teeth. Breakpoint mapping on the derivative chromosome 20 indicated that here the rearrangement disrupted the chromodomain helicase DNA binding protein 6 (CHD6) gene. To date, there is no indication that CHD6 is involved in disease. Our study indicates that TCF4 gene mutations are not always associated with classical PHS but can give rise to a much milder clinical phenotype. Thus, the possibility exists that more patients with a less severe encephalopathy carry a mutation in this gene.

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    ABSTRACT: Background Single nucleotide polymorphisms in TCF4 gene have been consistently associated with schizophrenia in genome wide association studies, including the C allele of rs9960767. However, its exact role in modulating the schizophrenia phenotype is not known. Aims To comprehensively investigate the relationship between rs9960767 risk allele (C) of TCF4 and cognitive performance in patients with first episode psychosis (FEP). Methods 173 patients with FEP received a comprehensive neurocognitive evaluation and were genotyped for rs9960767. Carriers of the risk allele (CA/CC) were compared to non-carriers (AA) using Multivariate Analysis of Covariance MANCOVA. Ethnicity, negative symptoms and substance abuse were included as covariates. Results Carriers of the risk allele had a statistically significant lower performance in the cognitive domain of Reasoning/Problem-Solving compared to non-carriers (F1,172 = 4.4, p = .038). There were no significant genotype effects on the other cognitive domains or general cognition. This effect on the Reasoning/Problem-Solving domain remained significant even when controlling for IQ (F1,172 = 4.3, p = .039). Conclusions rs9960767 (C) of TCF4 appears to be associated with neurocognitive deficits in the Reasoning/Problem-Solving cognitive domain, in patients with FEP. A confirmation of this finding in a larger sample and including other TCF4 polymorphisms will be needed to gain further validity of this result.
    Schizophrenia Research 01/2013; 152(1). DOI:10.1016/j.schres.2013.10.038 · 4.43 Impact Factor
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    ABSTRACT: The control of transcription is regulated through the well -coordinated spatial and temporal interactions between distal genomic regulatory elements required for specialized cell-type and developmental gene expression programs. With recent findings CFTR has served as a model to understand the principles that govern genome -wide and topological organization of distal intra -chromosomal contacts as it relates to transcriptional control. This is due to the extensive characterization of the DNase hypersensitivity sites, modification of chromatin, transcription factor binding sites and the arrangement of these sites in CFTR consistent with the restrictive expression in epithelial cell types. Here, we identified CHD6 from a screen among several chromatin-remodeling proteins as a putative epigenetic modulator of CFTR expression. Moreover, our findings of CTCF interactions with CHD6 are consistent with the role described previously for CTCF in CFTR regulation. Our results now reveal that the CHD6 protein lies within the infrastructure of multiple transcriptional complexes, such as the FACT, PBAF, PAF1C, Mediator, SMC/Cohesion, and MLL complexes. This model underlies the fundamental role CHD6 facilitates tethering cis -acting regulatory elements of CFTR in proximity to these multi-subunit transcriptional protein complexes. Finally, we indicate that CHD6 structurally coordinates a three -dimensional (3D) structure of intragenic elements of CFTR bound by several cell-type specific transcription factors, such as CDX2, SOX18, HNF4α, and HNF1α. Therefore, our results reveal new insights into the epigenetic regulation of CFTR expression and they may be useful for novel approaches for specific indications of cystic fibrosis and/or pancreatitis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 01/2015; DOI:10.1093/hmg/ddv032 · 6.68 Impact Factor
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    ABSTRACT: It is clear that the dermal papilla cell (DPC), which is located at the bottom of the hair follicle, is a special mesenchymal component, and it plays a leading role in regulating hair follicle development and periodic regeneration. Recent studies showed that the Wnt signaling pathway through β-catenin (canonical Wnt signaling pathway) is an essential component in maintaining the hair-inducing activity of the dermal papilla and growth of hair papilla cells. However, the intrinsic pathways and regulating mechanism are largely unknown. In the previous work, we constructed a cDNA subtractive library of DPC and first found that the TCF4 gene, as a key factor of Wnt signaling pathway, was expressed as the upregulated gene of the hair follicle in low-passage DPC. This study was to explore the role of TCF4 in regulating the proliferation and secretory activity of DPC. We constructed a pcDNA3.0-TCF4 expression vector and transfected it into DPC to achieve stable expression by bangosome 2000. Furthermore, we used the method of chemosynthesis to synthesize three pairs of TCF4 siRNA and transfected them into DPC. Meanwhile, we compared the transfection group and non-transfection group. We first proposed that there was expression difference in TCF4 in DPC under different biological condition. This study may have a high impact on the molecular mechanism of follicular lesions and provide a new vision for the treatment of clinic diseases.
    The Journal of Dermatology 12/2013; 41(1). DOI:10.1111/1346-8138.12313 · 2.35 Impact Factor


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