Multiple mutations in mouse Chd7 provide models for CHARGE syndrome
Multiple mutations in mouse Chd7 provide models for CHARGE syndrome
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DOI：
10.1093/hmg/ddi375
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发表时间：
2005-11-15
影响因子：
3.5
通讯作者：
Steel, KP
中科院分区：
文献类型：
--
作者：
Bosman, EA;Penn, AC;Steel, KP
小鼠ENU诱变方案已经在近端4号染色体上产生了一系列独立的突变，导致由于内耳外半规管截短而导致的显性头部摆动和盘旋行为。在这里，我们报告的识别突变的Chd7基因在9个这些突变等位基因，包括6个无义和3个剪接位点突变。已知人CHD7基因与CHARGE综合征有关，CHARGE综合征还表现出内耳畸形和各种其他特征，具有不同的遗传率，似乎是由于频繁的从头突变。我们发现Chd7在CHARGE综合征小鼠的早期发育中在受影响的器官中广泛表达，包括眼睛、嗅上皮、内耳和血管系统。对杂合突变小鼠的仔细检查发现了一系列缺陷，如腭裂、后鼻孔闭锁、心脏间隔缺损、出血、产前死亡、外阴和阴蒂缺陷以及干燥性角结膜炎。这些缺陷中的许多模仿CHARGE综合征的特征。该基因没有明显的特征，可能使它比其他基因更易变。我们的结论是，大量的小鼠突变体和人类的从头突变可能是由于Chd7基因是一个大的目标和事实，许多杂合子携带者的突变是可行的个人与一个容易检测的表型的组合。
Mouse ENU mutagenesis programmes have yielded a series of independent mutations on proximal chromosome 4 leading to dominant head-bobbing and circling behaviour due to truncations of the lateral semicircular canal of the inner ear. Here, we report the identification of mutations in the Chd7 gene in nine of these mutant alleles including six nonsense and three splice site mutations. The human CHD7 gene is known to be involved in CHARGE syndrome, which also shows inner ear malformations and a variety of other features with varying penetrance and appears to be due to frequent de novo mutation. We found widespread expression of Chd7 in early development of the mouse in organs affected in CHARGE syndrome including eye, olfactory epithelium, inner ear and vascular system. Closer inspection of heterozygous mutant mice revealed a range of defects with reduced penetrance, such as cleft palate, choanal atresia, septal defects of the heart, haemorrhages, prenatal death, vulva and clitoral defects and keratoconjunctivitis sicca. Many of these defects mimic the features of CHARGE syndrome. There were no obvious features of the gene that might make it more mutable than other genes. We conclude that the large number of mouse mutants and human de novo mutations may be due to the combination of the Chd7 gene being a large target and the fact that many heterozygous carriers of the mutations are viable individuals with a readily detectable phenotype.