A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C
A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C
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DOI：
10.1038/79171
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发表时间：
2000-09-01
期刊：
影响因子：
30.8
通讯作者：
Petit, C
中科院分区：
文献类型：
--
作者：
Verpy, E;Leibovici, M;Petit, C
Usher综合征1型（USH1）是一种常染色体隐性感觉缺陷，包括先天性深度感音神经性耳聋、前庭功能障碍和失明（由进行性视网膜色素变性引起）(1)。已经报道了6个不同的USH1基因座。到目前为止，只有编码MYO7A （USH1B）的MYO7A（参考文献2）被确定为突变导致该疾病的基因。在这里，我们报告了一个潜在的USH1基因（MIM 276904），这是一种USH1亚型，在路易斯安那州的阿卡迪亚后裔人群中(3)和黎巴嫩家庭中(4)被描述。我们从内耳感觉区提取的小鼠cDNA文库中鉴定出该基因（USH1C），编码含有pdz结构域的蛋白和声素。在患者中，我们发现了一个剪接位点突变，一个移码突变和一个内含子可变数目串联重复序列（VNTR）的扩增。我们发现，在老鼠的内耳中，只有感觉毛细胞表达和谐素。内耳Ush1c转录本预测了几种和谐蛋白异构体，其中一些含有额外的螺旋结构域和富含脯氨酸和丝氨酸的区域。由于这些转录本中有几个在眼睛中缺失，我们认为USH1C也是DFNB18形式孤立性耳聋的基础。
Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)(1). Six different USH1 loci have been reported. So far, only MYO7A (USH1B), encoding myosin VIIA (ref. 2), has been identified as a gene whose mutation causes the disease. Here, we report a gene underlying USH1C (MIM 276904), a USH1 subtype described in a population of Acadian descendants from Louisiana(3) and in a Lebanese family(4). We identified this gene (USH1C), encoding a PDZ-domain-containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas. In patients we found a splice-site mutation, a frameshift mutation and the expansion of an intronic variable number of tandem repeat (VNTR). We showed that, in the mouse inner ear, only the sensory hair cells express harmonin. The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region. As several of these transcripts were absent from the eye, we propose that USH1C also underlies the DFNB18 form of isolated deafness.