Abstract
TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt–Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.
Highlights
AND OVERVIEW Pitt–Hopkins Syndrome (PTHS) is a rare disorder characterized by intellectual disability (ID), ‘atypical’ autistic characteristics, and hyperventilation
Forrest et al tested a panel of PTHS-associated mutations and found that mutations in the bHLH domain of transcription factor 4 (TCF4) alter the subnuclear localization of TCF4 and regulated homo- and heterodimer formation. They found that TCF4 can transactivate the NRXN1b and contactin-associated protein-like 2 (CNTNAP2) promoters using in vitro fluorescent reporter constructs and using this experimental system observed variable, context-specific deficits in the ability of the different PTHS-associated TCF4 mutants to activate gene transcription when coexpressed with different bHLH transcription factors. These interesting observations demonstrated that PTHS-associated missense mutations can have multiple effects on the function of TCF4 and, as described above, suggest that TCF4 may modulate the expression of NRXN1 and CNTNAP2, thereby defining a regulatory network in PTHS and PTHS-like ID syndromes
SUMMARY AND FUTURE DIRECTIONS PTHS is a rare human mental retardation syndrome associated with profound deficits in general learning and memory and an almost complete lack of language learning
Summary
AND OVERVIEW Pitt–Hopkins Syndrome (PTHS) is a rare disorder characterized by intellectual disability (ID), ‘atypical’ autistic characteristics, and hyperventilation. Hyperventilation can be followed by apnea, but apnea can occur independent from hyperventilation.[22,24,29,38] one very recent report identified a bona fide case of Pitt–Hopkins Syndrome, confirmed by genetic diagnostics, of a 12-year-old boy presenting with psychomotor retardation, recurrent respiratory tract infections and typical dysmorphic features but with absence of hyperventilation or other breathing abnormalities.
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