caa a22 4500 445861061 CHVBK 20180317145443.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s00439-011-0999-4 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0999-4 Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model [Elektronische Daten] [Antje Brockschmidt, Alida Filippi, Peter Charbel Issa, Michael Nelles, Horst Urbach, Nicole Eter, Wolfgang Driever, Ruthild Weber] 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 9years 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. Springer-Verlag, 2011 Brockschmidt Antje Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut Filippi Alida Department of Developmental Biology, Faculty of Biology, Albert-Ludwigs-University Freiburg, Hauptstrasse 1, 79104, Freiburg, Germany aut Charbel Issa Peter Department of Ophthalmology, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut Nelles Michael Department of Radiology/Neuroradiology, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut Urbach Horst Department of Radiology/Neuroradiology, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut Eter Nicole Department of Ophthalmology, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut Driever Wolfgang Department of Developmental Biology, Faculty of Biology, Albert-Ludwigs-University Freiburg, Hauptstrasse 1, 79104, Freiburg, Germany aut Weber Ruthild Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut Human Genetics Springer-Verlag 130/5(2011-11-01), 645-655 0340-6717 130:5<645 2011 130 439 https://doi.org/10.1007/s00439-011-0999-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0999-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Brockschmidt Antje Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut NATIONALLICENCE 700 1- Filippi Alida Department of Developmental Biology, Faculty of Biology, Albert-Ludwigs-University Freiburg, Hauptstrasse 1, 79104, Freiburg, Germany aut NATIONALLICENCE 700 1- Charbel Issa Peter Department of Ophthalmology, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut NATIONALLICENCE 700 1- Nelles Michael Department of Radiology/Neuroradiology, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut NATIONALLICENCE 700 1- Urbach Horst Department of Radiology/Neuroradiology, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut NATIONALLICENCE 700 1- Eter Nicole Department of Ophthalmology, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut NATIONALLICENCE 700 1- Driever Wolfgang Department of Developmental Biology, Faculty of Biology, Albert-Ludwigs-University Freiburg, Hauptstrasse 1, 79104, Freiburg, Germany aut NATIONALLICENCE 700 1- Weber Ruthild Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Sigmund-Freud-Str. 25, 53105, Bonn, Germany aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 130/5(2011-11-01), 645-655 0340-6717 130:5<645 2011 130 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer