Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model
Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model
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DOI：
10.1007/s00439-011-0999-4
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发表时间：
2011-11-01
期刊：
影响因子：
5.3
通讯作者：
Weber, Ruthild G.
中科院分区：
文献类型：
--
作者：
Brockschmidt, Antje;Filippi, Alida;Weber, Ruthild G.
在这项研究中，我们对一名皮特-霍普金斯综合征(PTHS)患者的神经学和眼科表型进行了深入分析，并研究了斑马鱼模型。PTHS是一种以严重的精神和运动发育迟缓为特征的疾病，携带单等位基因TCF4缺失。PTHS患者的特征是高分辨率磁共振成像(MRI)和扩散张量成像来分析大脑的结构，光谱域光学相干断层扫描来可视化视网膜层，以及视网膜电描记术来评估视网膜功能。通过在斑马鱼胚胎中注射吗啡诺反义寡核苷酸来敲除TCF4功能，建立了斑马鱼模型，并对其神经分化基因Neurg1、ascl1b、pax6a、zic1、atoh1a、atoh2b的表达进行了表型分析。对PTHS患者和斑马鱼变种的数据进行了比较。虽然脑MRI扫描显示1岁PTHS患者髓鞘形成明显延迟和脑室增大，但9岁时未发现包括白质束改变在内的结构性脑异常。眼部结构检查显示高度近视，眼球长度增加，而视网膜层正常。斑马鱼胚胎中TCF4功能的敲除导致脑和眼睛的终末分化发育延迟或缺陷，小眼睛的眼长相对增加，后脑室增大。综上所述，斑马鱼胚胎中的TCF4基因敲除似乎不影响早期的神经模式和前脑的区域化，但可能参与神经发生和分化的后期方面。我们为TCF4/E2-2在PTHS患者和斑马鱼模型的眼生长控制中的作用提供了证据。
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.