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Y.-W. Peng, M. Zallocchi, D. E. Cosgrove; Retinal Degeneration in Usher Syndrome Type IIa. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2492.
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Usher syndrome type IIa is the most common of the Usher syndromes, and thus the leading single genetic cause of combined deafness and blindness in the world. The gene responsible encodes two different protein isoforms called usherin. The short isoform of usherin binds integrin α1ß1 receptors. This study was designed to test the hypothesis that usherin interaction with α1ß1 integrin on the retinal pigment epithelium (RPE) is central to usherin function in the retina, and absence of this interaction is a contributing factor in USH2a retinal pathogenesis.
Immunoprecipitation and immunoblotting were used to identify the interactions between usherin and integrin receptors. Gene targeting was used to produce an usherin hypomorph mouse model. Immunohistochemistry, immunoblotting and eletroretinogram (ERG) were used to study the retinal degeneration and protein translocation.
The thrombospondin domain of the short isoform of usherin binds integrin α1ß1 receptors at the juncture between the basement membrane of Bruch’s layer and the basal processes of the RPE. A specific point mutation that results in an arginine substitution for glycine at amino acid 268 (in humans) abolishes this interaction. In humans, this mutation is pathologic. Using gene targeting in ES cells we have created an usherin hypomorph mouse model. We compare the phenotype of this mouse model with an integrin α1 knockout mouse. The results indicate that specific aspects of retinal degeneration in these two mouse models are surprisingly similar. Both animals show markedly diminished ERG responses. In addition, both show marked thickening of the basement membrane in Bruch’s layer associated with retraction of the basal processes of the RPE, distinct photoreceptor synaptic malformations, and progressive loss of photoreceptors with similar time course. Furthermore, both animals models show markedly slowed translocation of transducin and arrestin in rod photoreceptors following light exposure of dark adapted animals, even in very young animals.
Both usherin hypomorph mice and integrin α1-null mice exhibit remarkably similar features of retinal pathology, suggesting usherin-mediated signaling though α1ß1 integrin on RPE cells is required to regulate normal basement membrane metabolism, and that absence of this interaction may result in USH2a retinal pathogenesis.
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