Genetics of Presbyacus's and its clinical application

老年痴呆症的遗传学及其临床应用

• 批准号: 10307039
• 负责人: TAKASAKA Tomonori
• 金额: $ 22.08万
• 依托单位: TOHOKU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10307039/
• 关键词: knockout mice; Brain-4; Connexin-26; Endocochlear potential; Hereditary deafness; Aging; DNA mutation; 老人性難聴; ミトコンドリアDNA; 老化マウス; 変異; 内耳; Brn4; 加齢

DFN3, and 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 indicated 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ィイD1+ィエD1 homeostasis, may play a critical role in auditory function and show a major cause of the hereditary deafness.

DFN 3和X连锁非综合征型混合性耳聋是由编码POU转录因子基因的BRN-4基因突变引起的。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，这是间充质起源，并已被假定为在K β D1+ β D1稳态的功能，可能在听觉功能中发挥关键作用，并显示遗传性耳聋的主要原因。

项目成果

Goto et al.: "Expression and localization of the Na+-H+exchanger"Hear res. 128. 89-96 (1999)

Goto 等人：“Na -H 交换器的表达和定位”听资源。

Kudo et al.: "New Common mutations in the GJB2"Am J Med Genet. 90. 141-145 (2000)

Kudo 等人：“GJB2 中的新常见突变”Am J Med Genet。

Kudo et al.: "New Commom mutations in the GTB2"Am J Med Genet. 90. 141-145 (2000)

Kudo 等人：“GTB2 中的新常见突变”Am J Med Genet。

Oshima T et al: "Hearing loss with a mitochondnial gene" Laryngoscope. (印刷中).

Oshima T 等人：“线粒体基因导致的听力损失”喉镜（正在出版）。

Ueda N et al: "Mitochondrial DNA deletion" Laryngoscope. 108. 580-584 (1998)

Ueda N 等人：“线粒体 DNA 缺失”喉镜。