Verpy E, Leibovici M, Zwaenepoel I, Liu X Z, Gal A, Salem N, Mansour A, Blanchard S, Kobayashi I, Keats B J, Slim R, Petit C
Unité de Génétique des Déficits Sensoriels, CNRS URA 1968, Institut Pasteur, Paris cedex 15, France.
Nat Genet. 2000 Sep;26(1):51-5. doi: 10.1038/79171.
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, 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 and in a Lebanese family. 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.
1型Usher综合征（USH1）是一种常染色体隐性感觉缺陷，涉及先天性重度感音神经性耳聋、前庭功能障碍和失明（由于进行性视网膜色素变性）。已报道了6个不同的USH1位点。到目前为止，仅编码肌球蛋白VIIA的MYO7A（USH1B）已被鉴定为其突变导致该病的基因。在此，我们报道了USH1C（MIM 276904）的一个相关基因，USH1C是在路易斯安那州阿卡迪亚后裔群体和一个黎巴嫩家族中描述的一种USH1亚型。我们在一个源自内耳感觉区域的消减小鼠cDNA文库中鉴定出了这个编码含PDZ结构域蛋白harmonin的基因（USH1C）。在患者中，我们发现了一个剪接位点突变、一个移码突变以及一个内含子可变数目串联重复序列（VNTR）的扩增。我们发现，在小鼠内耳中，只有感觉毛细胞表达harmonin。内耳Ush1c转录本预测了几种harmonin异构体，其中一些含有额外的卷曲螺旋结构域和富含脯氨酸及丝氨酸的区域。由于这些转录本中的几种在眼中不存在，我们提出USH1C也是孤立性耳聋DFNB18型的病因。
