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Gene transfer to a animal model of deafness gene mutation and its clinical application

耳聋基因突变动物模型基因转入及其临床应用

基本信息

批准号：
11557122
负责人：
IKEDA Katsuhisa
金额：
$ 7.1万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557122/
关键词：
Deafness gene Mutation Brn-4 GJB2 Konckout mice Gen transfer Endocochlear potential K recysling ブレイン-4 遺伝子移入遺伝子難聴 Brn-4 内リンパ静止電位 K^+イオン

项目摘要

DFN3, an X-linked nonsyndromic mixed deafness is caused by mutations in BRN-4 gene, which encodes a POU transcription factor gene. By gene targeting technology Brn-4-deficient mice were created and found to exhibit profound deafness. No gross morphological changes were observed in the conductive ossicles or cochlea, although there was a drastic reduction in endocochlear potential (EP). Electron microscopy revealed severe ultrastructural alterations in cochlear spiral ligament fibrocytes. Connexin 26 gene (GJB2) is known to be expressed in the cochlear fibrocytes and to play a important role in the auditory function. We have sequenced the GJB2 gene in 39 Japanese patients with prelingual sensorineural hearing loss. Three novel mutations were identified : a single nucleotide deletion (235delC), a 16 bp-deletion (176-191 del (16)) and a nonsense mutation (408c>a) in five unrelated patients. These findings indicate that GJB2 mutations are also responsible for prelingual deafness in Japan. These findings suggest that these fibrocytes, which are mesenchymal in origin and have been postulated to function in K^+ homeostasis, may play a critical role in auditory function and show a major cause of the hereditary deafness.

DFN 3是一种X连锁非综合征型混合性耳聋，由编码POU转录因子基因的BRN-4基因突变引起。通过基因靶向技术，创建了Brn-4缺陷小鼠，并发现其表现出严重的耳聋。虽然耳蜗内电位（EP）显著降低，但传导性听小骨或耳蜗没有明显的形态学变化。电子显微镜显示严重的耳蜗螺旋韧带纤维细胞的超微结构改变。缝隙连接蛋白26基因（Connexin 26 gene，GJB 2）在耳蜗纤维细胞中表达，在听觉功能中起重要作用。我们对39例日本语前感音神经性耳聋患者的GJB 2基因进行了测序。在5名无关患者中发现了3种新的突变：单核苷酸缺失（235 delC）、16 bp缺失（176-191 del（16））和无义突变（408 c>a）。这些发现表明，GJB 2突变也是日本语前耳聋的原因。这些发现表明，这些纤维细胞起源于间充质，被认为在K^+体内平衡中发挥作用，可能在听觉功能中发挥关键作用，并显示出遗传性耳聋的主要原因。