Reiners Jan, Nagel-Wolfrum Kerstin, Jürgens Karin, Märker Tina, Wolfrum Uwe
Institute of Zoology, Department of Cell and Matrix Biology, Johannes Gutenberg University of Mainz, Müllerweg 6, D-55099 Mainz, Germany.
Exp Eye Res. 2006 Jul;83(1):97-119. doi: 10.1016/j.exer.2005.11.010. Epub 2006 Mar 20.
Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. It is clinically and genetically heterogeneous and at least 12 chromosomal loci are assigned to three clinical USH types, namely USH1A-G, USH2A-C, USH3A (Davenport, S.L.H., Omenn, G.S., 1977. The heterogeneity of Usher syndrome. Vth Int. Conf. Birth Defects, Montreal; Petit, C., 2001. Usher syndrome: from genetics to pathogenesis. Annu. Rev. Genomics Hum. Genet. 2, 271-297). Mutations in USH type 1 genes cause the most severe form of USH. In USH1 patients, congenital deafness is combined with a pre-pubertal onset of retinitis pigmentosa (RP) and severe vestibular dysfunctions. Those with USH2 have moderate to severe congenital hearing loss, non-vestibular dysfunction and a later onset of RP. USH3 is characterized by variable RP and vestibular dysfunction combined with progressive hearing loss. The gene products of eight identified USH genes belong to different protein classes and families. There are five known USH1 molecules: the molecular motor myosin VIIa (USH1B); the two cell-cell adhesion cadherin proteins, cadherin 23 (USH1D) and protocadherin 15, (USH1F) and the scaffold proteins, harmonin (USH1C) and SANS (USH1G). In addition, two USH2 genes and one USH3A gene have been identified. The two USH2 genes code for the transmembrane protein USH2A, also termed USH2A ("usherin") and the G-protein-coupled 7-transmembrane receptor VLGR1b (USH2C), respectively, whereas the USH3A gene encodes clarin-1, a member of the clarin family which exhibits 4-transmembrane domains. Molecular analysis of USH1 protein function revealed that all five USH1 proteins are integrated into a protein network via binding to PDZ domains in the USH1C protein harmonin. Furthermore, this scaffold function of harmonin is supported by the USH1G protein SANS. Recently, we have shown that the USH2 proteins USH2A and VLGR1b as well as the candidate for USH2B, the sodium bicarbonate co-transporter NBC3, are also integrated into this USH protein network. In the inner ear, these interactions are essential for the differentiation of hair cell stereocilia but may also participate in the mechano-electrical signal transduction and the synaptic function of maturated hair cells. In the retina, the co-expression of all USH1 and USH2 proteins at the synapse of photoreceptor cells indicates that they are organized in an USH protein network there. The identification of the USH protein network indicates a common pathophysiological pathway in USH. Dysfunction or absence of any of the molecules in the mutual "interactome" related to the USH disease may lead to disruption of the network causing senso-neuronal degeneration in the inner ear and the retina, the clinical symptoms of USH.
乌谢综合征（USH）是人类致聋致盲合并症最常见的病因。它在临床和遗传方面具有异质性，至少12个染色体位点被归为三种临床USH类型，即USH1A - G、USH2A - C、USH3A（达文波特，S.L.H.，奥门，G.S.，1977年。乌谢综合征的异质性。第五届国际出生缺陷大会，蒙特利尔；佩蒂特，C.，2001年。乌谢综合征：从遗传学发病机制。《基因组学与人类遗传学年度评论》2，271 - 297）。USH1型基因的突变导致USH最严重的形式。在USH1患者中，先天性耳聋伴有青春期前视网膜色素变性（RP）发作和严重的前庭功能障碍。USH2患者有中度至重度先天性听力损失、非前庭功能障碍和较晚发作的RP。USH3的特征是RP和前庭功能障碍程度不一，伴有进行性听力损失。已鉴定的8个USH基因的基因产物属于不同的蛋白质类别和家族。有5种已知的USH1分子：分子运动蛋白肌球蛋白VIIa（USH1B）；两种细胞间黏附钙黏蛋白，钙黏蛋白23（USH1D）和原钙黏蛋白15（USH1F），以及支架蛋白，和声蛋白（USH1C）和SANS（USH1G）。此外，已鉴定出两个USH2基因和一个USH3A基因。这两个USH2基因分别编码跨膜蛋白USH2A，也称为USH2A（“乌谢蛋白”）和G蛋白偶联的7跨膜受体VLGR1b（USH2C），而USH3A基因编码克拉林 - 1，它是克拉林家族的成员，具有4个跨膜结构域。USH1蛋白质功能的分子分析表明，所有5种USH1蛋白质通过与USH1C蛋白和声蛋白中的PDZ结构域结合而整合到一个蛋白质网络中。此外，USH1G蛋白SANS支持和声蛋白的这种支架功能。最近，我们已经表明，USH2蛋白USH2A和VLGR1b以及USH2B的候选蛋白，碳酸氢钠共转运体NBC3，也整合到这个USH蛋白网络中。在内耳中，这些相互作用对于毛细胞静纤毛的分化至关重要，但也可能参与成熟毛细胞的机械电信号转导和突触功能。在视网膜中，所有USH1和USH2蛋白在光感受器细胞突触处的共表达表明它们在那里组织成一个USH蛋白网络。USH蛋白网络的鉴定表明USH存在共同的病理生理途径。与USH疾病相关的相互“相互作用组”中任何分子的功能障碍或缺失都可能导致网络破坏，从而导致内耳和视网膜中的感觉神经元变性，即USH的临床症状。
