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Reiners, J., Nagel-Wolfrum, K., Jurgens, K., Marker, T. & Wolfrum, U. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp. Eye Res. 83, 97-119

Department of Cell and Matrix Biology, Johannes Gutenberg-Universität Mainz, Mayence, Rheinland-Pfalz, Germany
Experimental Eye Research (Impact Factor: 3.02). 08/2006; 83(1):97-119. DOI: 10.1016/j.exer.2005.11.010
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ABSTRACT 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.

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    • "The USH1 retinopathy is classified as a rod-cone dystrophy, in which rod anomalies appear first and rapidly worsen, followed by a slow progressing cone dysfunction, and photoreceptor cell degeneration [9,13–17]. Night blindness may be detected during childhood , and this can be followed by a narrowing of the visual field (''tunnel vision''), which rapidly progresses to more severe blindness [2] [18]. Retinal degeneration over the course of the disorder can be followed by the progressive reduction in electroretinogram (ERG) wave amplitudes and by fundus examination. "
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    ABSTRACT: The Usher syndrome (USH) is the most prevalent cause of inherited deaf-blindness. Three clinical subtypes, USH1-3, have been defined, and ten USH genes identified. The hearing impairment due to USH gene defects has been shown to result from improper organisation of the hair bundle, the sound receptive structure of sensory hair cells. In contrast, the cellular basis of the visual defect is less well understood as this phenotype is absent in almost all the USH mouse models that faithfully mimic the human hearing impairment. Structural and molecular interspecies discrepancies regarding photoreceptor calyceal processes and the association with the distribution of USH1 proteins have recently been unravelled, and have led to the conclusion that a defect in the USH1 protein complex-mediated connection between the photoreceptor outer segment and the surrounding calyceal processes (in both rods and cones), and the inner segment (in rods only), probably causes the USH1 retinal dystrophy in humans.
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    • "Thus, protein function is reestablished despite of a possible incorrect amino acid incorporated in the recovered harmonin. Interestingly, incorporation of faulty amino acids, as caused by missense mutations in USH1C, results only in isolated deafness but not in retinal degeneration (Ahmed et al, 2002; Ouyang et al, 2002; Reiners et al, 2006; Yan & Liu, 2010). Based on the phenotypegenotype correlation, any TRID-mediated read-through of the p.R31X mutation in USH1C may be sufficient for the restoration of retinal function. "
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    • "PDZ domains constitute a large family of globular domains found in prokaryotes and eukaryotes [3] with about 270 occurrences in the human proteome (see next section). PDZ-domain containing proteins are implicated in diverse cellular functions such as establishment and maintenance of cell polarity [4], signal transmission in neurons [5] or in visual and auditive processes in the eye and ear [6] [7], cell migration [8], and regulation of cell junctions [9] (for reviews see [10] [11]). "
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