Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects
Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects
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DOI：
10.1093/hmg/10.22.2549
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发表时间：
2001-10-15
影响因子：
3.5
通讯作者：
Morrow, BE
中科院分区：
文献类型：
--
作者：
Funke, B;Epstein, JA;Morrow, BE
Velo-cardio-facial syndrome/DiGeorge syndrome（VCFS/DGS）是一种与半合子22 q11缺失相关的先天性异常疾病。我们先前表明，细菌人工染色体（BAC）转基因小鼠过表达四个转基因，PNUTL 1，（CDCrel-1），GP 1B β，TBX 1和WDR 14，有降低的生存能力，心血管畸形和胸腺发育不全。由于这些是VCFS/DGS的标志性特征，我们分析了小鼠的其他异常。我们发现，小鼠在中耳和内耳有重要的缺陷，这些缺陷与这种疾病直接相关。最显著的缺陷是慢性中耳炎的存在，这是VCFS/DGS患者的常见发现。此外，小鼠具有过度活跃的盘旋行为和感音神经性听力损失。这与中耳和内耳畸形有关，类似于报告发生在VCFS/DGS患者中的人类Mondini发育不良。我们认为一种或多种转基因的过度表达是导致小鼠耳缺损的病因。根据其在耳中的表达模式和基因的功能研究，TbX 1可能起着核心作用。TBX 1单倍不足可能是VCFS/DGS患者耳部疾病的原因。
Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the transgenes is responsible for the etiology of the ear defects in the mice. Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.