title: Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model.
abstract: In this study, we performed an in-depth analysis of the neurologic and ophthalmologic phenotype in a patient with Pitt-Hopkins syndrome (PTHS), a disorder characterized by severe mental and motor retardation, carrying a uniallelic TCF4 deletion, and studied a zebrafish model. The PTHS-patient was characterized by high-resolution magnetic resonance imaging (MRI) with diffusion tensor imaging to analyze the brain structurally, spectral-domain optical coherence tomography to visualize the retinal layers, and electroretinography to evaluate retinal function. A zebrafish model was generated by knockdown of tcf4-function by injection of morpholino antisense oligos into zebrafish embryos and the morphant phenotype was characterized for expression of neural differentiation genes neurog1, ascl1b, pax6a, zic1, atoh1a, atoh2b. Data from PTHS-patient and zebrafish morphants were compared. While a cerebral MRI-scan showed markedly delayed myelination and ventriculomegaly in the 1-year-old PTHS-patient, no structural cerebral anomalies including no white matter tract alterations were detected at 9 years of age. Structural ocular examinations showed highly myopic eyes and an increase in ocular length, while retinal layers were normal. Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes, small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. In summary, tcf4-knockdown in zebrafish embryos does not seem to affect early neural patterning and regionalization of the forebrain, but may be involved in later aspects of neurogenesis and differentiation. We provide evidence for a role of TCF4/E2-2 in ocular growth control in PTHS-patients and the zebrafish model.
authors.affiliation: Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Brockschmidt
authors.forename: Alida
authors.initials: A
authors.lastname: Filippi
authors.forename: Peter
authors.initials: P
authors.lastname: Charbel Issa
authors.forename: Michael
authors.initials: M
authors.lastname: Nelles
authors.forename: Horst
authors.initials: H
authors.lastname: Urbach
authors.forename: Nicole
authors.initials: N
authors.lastname: Eter
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Driever
authors.forename: Ruthild G
authors.initials: RG
authors.lastname: Weber
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D001921:Brain / Q000648:ultrastructure*; D004195:Disease Models, Animal; D004596:Electroretinography; D005123:Eye / Q000254:growth & development / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics / Q000473:pathology; D019066:Facies; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D006985:Hyperventilation / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics; D011859:Radiography; D012160:Retina / Q000254:growth & development / Q000503:physiopathology / Q000648:ultrastructure*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; C517154:Tcf4 protein, zebrafish; D000073940:Transcription Factor 4; D014157:Transcription Factors; D029961:Zebrafish Proteins