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

DFN3是一种X连锁的非综合征性混合性耳聋，由编码POU转录因子基因的BRN-4基因突变引起。通过基因打靶技术，培育出了BRN-4缺陷小鼠，并发现它们表现出严重的耳聋。耳蜗内电位(EP)显著降低，但传导性听小骨或耳蜗区未见大体形态改变。电子显微镜下可见耳蜗螺旋韧带纤维细胞超微结构严重改变。连接蛋白26基因(GJB2)在耳蜗肌纤维细胞中表达，在听觉功能中发挥重要作用。我们对39例日本语前感音神经性聋患者的GJB2基因进行了测序。在5例无关患者中发现了3个新的突变：单核苷酸缺失(235delC)、16bp缺失(176-191 del(16))和无义突变(408C&gt；a)。这些发现表明，GJB2突变也是日本语前性耳聋的原因。这些发现表明，这些起源于间充质的纤维细胞可能在听功能中起关键作用，并可能是遗传性耳聋的主要原因。

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.