title: 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.
authors.affiliation: 1Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, 53111 Bonn, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Brockschmidt
authors.forename: Unda
authors.initials: U
authors.lastname: Todt
authors.forename: Soojin
authors.initials: S
authors.lastname: Ryu
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Christina
authors.initials: C
authors.lastname: Landwehr
authors.forename: Stefanie
authors.initials: S
authors.lastname: Birnbaum
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Frenck
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Driever
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Ruthild G
authors.initials: RG
authors.lastname: Weber
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002648:Child; D020732:Cytogenetic Analysis; D004268:DNA-Binding Proteins; D005145:Face / Q000002:abnormalities; D005260:Female; D006239:Haplotypes; D006801:Humans; D006985:Hyperventilation / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D007805:Language Development Disorders / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D013577:Syndrome; D051820:TCF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D015027:Zebrafish / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051820:TCF Transcription Factors; C532096:TCF4 protein, human; C544894:TCF7L2 protein, human; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors