Severe mental retardation with breathing abnormalities (Pitt–Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4
Abstract
Pitt-Hopkins syndrome (PHS) is a rare syndromic mental disorder, which is mainly characterized by severe motor and mental retardation including absent language development, a characteristic facial gestalt and episodes of hyperventilation. We report on a female patient with PHS showing severe mental retardation with absent speech, pronounced muscular hypotonia, ataxia, distinctive facial features, such as a coarse face, a broad nasal bridge and a wide mouth, and hyperventilation attacks. In this patient, genomic profiling by array-based comparative genomic hybridization and fluorescence in situ hybridization studies detected and confirmed a de novo 0.5 Mb deletion in 18q21.2 containing a single gene, the basic helix-loop-helix transcription factor TCF4. cDNA and genomic analyses in the patient and her parents demonstrated TCF4 haploinsufficiency as the underlying cause of the disease. Analysis of the embryonal expression pattern of the Danio rerio ortholog, tcf4, by whole-mount in situ hybridization showed a highly specific expression domain in the pallium of the telencephalon during late somitogenesis, when the patterning of the zebrafish brain is advanced and neural differentiation commences. Later expression domains were restricted to several regions in the central nervous system, including continued expression in the pallium of the telencephalon, and starting expression in the diencephalon (thalamus, ventral thalamus and posterior tuberculum), the midbrain tegmentum, the hindbrain and the branchial arches. This expression pattern correlates with the clinical phenotype. Our results show that haploinsufficiency of TCF4 causes PHS and suggest that D. rerio is a valuable model to study the molecular pathogenesis of PHS and the role of TCF4 in brain development.
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Mutations in DYRK1A and TCF4 cause syndromic diseases presenting with microcephaly and intellectual disability.
“Mutations in DYRK1A and TCF4 cause syndromic diseases presenting with microcephaly and intellectual disability97–105.”
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- Authors
- Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C., & Weber, R. G.
- Affiliations
- University of Bonn (DE)
- University of Cologne (DE)
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- Corresponding author
- Weber, Ruthild G.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-05-03
- Volume
- 16
- Issue
- 12
- Pages
- 1488-1494
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2155167158
- Cited by
- 170
- References
- 17
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 10 · 2023: 2 · 2022: 8 · 2021: 12 · 2020: 10 · 2019: 9 · 2018: 6 · 2017: 9 · 2016: 5 · 2015: 8 · 2014: 7 · 2013: 8 · 2012: 19
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Pitt-Hopkins syndrome, TCF4, haploinsufficiency, severe intellectual disability, hyperventilation, de novo deletion, bHLH transcription factors, brain development, pallium, telencephalon
- MeSH terms
- Transcription Factor 4, Animals, Child, DNA-Binding Proteins, Face, Female, Haplotypes, Humans, Hyperventilation, Language Development Disorders, Intellectual Disability, Models, Genetic, Mutation, Syndrome, Transcription Factors, Zebrafish, Cytogenetic Analysis, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein
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