Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain-dependent.
Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain-dependent.
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DOI：
10.1111/gbb.12839
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发表时间：
2023-06
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影响因子：
--
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CHARGE综合征是一种异质性疾病，其特征在于影响多个组织的一系列缺陷和行为困难，如自闭症、注意力缺陷/多动障碍、强迫症、焦虑和感觉缺陷。大多数CHARGE病例是由染色体结构域解旋酶DNA结合蛋白7（CHD 7）的新发功能丧失突变引起的。CHD 7是神经元分化和神经嵴细胞迁移等过程所必需的，但CHD 7如何影响神经回路功能以调节行为尚不清楚。为了研究CHARGE中行为症状的病理生理学，我们建立了一种突变的chd 7斑马鱼系，该斑马鱼系重现了多种CHARGE表型，包括耳、心脏和颅面缺陷。通过一组行为检测，我们发现chd 7突变体具有特定的听觉和视觉行为缺陷，这些缺陷独立于感觉结构的缺陷。Mauthner细胞依赖性短潜伏期声惊吓反应在chd 7突变体中是正常的，而Mauthner非依赖性长潜伏期反应减少。突变体对光线突然减少的反应也减少，而对光线突然增加的反应是正常的，这表明视网膜OFF通路可能受到影响。此外，通过分析多个chd 7等位基因，我们观察到形态和行为表型的突变率受遗传背景的影响，但它也取决于突变的位置，与chromodomain突变导致最高的突变率。这种模式与CHARGE患者数据集的分析一致，其中CHD 7染色体结构域突变的受试者的症状发生率最高。这些结果为CHARGE的异质性提供了新的见解，并将为未来定义CHD 7依赖性神经行为机制的工作提供信息。CHARGE综合征是一种由CHD 7突变引起的异质性疾病。新的斑马鱼模型概括了多种与CHARGE相关的形态和行为表型，并揭示了表型突变率取决于遗传背景和CHD 7内突变的位置。
CHARGE syndrome is a heterogeneous disorder characterized by a spectrum of defects affecting multiple tissues and behavioral difficulties such as autism, attention‐deficit/hyperactivity disorder, obsessive–compulsive disorder, anxiety, and sensory deficits. Most CHARGE cases arise from de novo, loss‐of‐function mutations in chromodomain‐helicase‐DNA‐binding‐protein‐7 (CHD7). CHD7 is required for processes such as neuronal differentiation and neural crest cell migration, but how CHD7 affects neural circuit function to regulate behavior is unclear. To investigate the pathophysiology of behavioral symptoms in CHARGE, we established a mutant chd7 zebrafish line that recapitulates multiple CHARGE phenotypes including ear, cardiac, and craniofacial defects. Using a panel of behavioral assays, we found that chd7 mutants have specific auditory and visual behavior deficits that are independent of defects in sensory structures. Mauthner cell‐dependent short‐latency acoustic startle responses are normal in chd7 mutants, while Mauthner‐independent long‐latency responses are reduced. Responses to sudden decreases in light are also reduced in mutants, while responses to sudden increases in light are normal, suggesting that the retinal OFF pathway may be affected. Furthermore, by analyzing multiple chd7 alleles we observed that the penetrance of morphological and behavioral phenotypes is influenced by genetic background but that it also depends on the mutation location, with a chromodomain mutation causing the highest penetrance. This pattern is consistent with analysis of a CHARGE patient dataset in which symptom penetrance was highest in subjects with mutations in the CHD7 chromodomains. These results provide new insight into the heterogeneity of CHARGE and will inform future work to define CHD7‐dependent neurobehavioral mechanisms. CHARGE syndrome is a heterogeneous condition caused by mutations in CHD7. New zebrafish models recapitulate multiple CHARGE‐related morphological and behavioral phenotypes and reveal that phenotype penetrance depends on both genetic background and the location of the mutation within CHD7.
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影响因子：
3.5
作者：
Bosman, EA;Penn, AC;Steel, KP
通讯作者：
Steel, KP
影响因子：
3.5
作者：
Asad, Zainab;Pandey, Aditi;Sachidanandan, Chetana
通讯作者：
Sachidanandan, Chetana
DOI：
10.1073/pnas.96.13.7558
发表时间：
1999-06-22
影响因子：
11.1
作者：
Alexandre, D;Ghysen, A
通讯作者：
Ghysen, A
影响因子：
5.3
作者：
Burgess, Harold A.;Granato, Michael
通讯作者：
Granato, Michael
影响因子：
2.7
作者：
Alavizadeh, A;Kiernan, AE;Bucan, M
通讯作者：
Bucan, M