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Ferry F. J. Kersten, Erwin van Wijk, Jeroen van Reeuwijk, Bert van der Zwaag, Tina Märker, Theo A. Peters, Nicholas Katsanis, Uwe Wolfrum, Jan E. E. Keunen, Ronald Roepman, Hannie Kremer; Association of Whirlin with Cav1.3 (α1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network. Invest. Ophthalmol. Vis. Sci. 2010;51(5):2338-2346. doi: 10.1167/iovs.09-4650.
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Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ-binding motif. These proteins co-localize with whirlin at the region of the connecting cilium and at the synapse of photoreceptor cells. This study was undertaken to identify novel, Usher syndrome-associated, interacting partners of whirlin and thereby obtain more insights into the function of whirlin.
The database of ciliary proteins was searched for proteins that are present in both the retina and inner ear and contain a PDZ-binding motif. Interactions with whirlin were evaluated by yeast two-hybrid analyses and validated by glutathione S-transferase pull-down assays, co-immunoprecipitation, and co-localization in the retina with immunofluorescence and immunoelectron microscopy.
The L-type calcium channel subunit Cav1.3 (α1D) specifically interacts with whirlin. In adult photoreceptors, Cav1.3 (α1D) and whirlin co-localize in the region of the connecting cilium and at the synapse. During murine embryonic development, the expression patterns of the Whrn and Cacna1d genes show significant overlap and include expression in the eye, the inner ear, and the central nervous system.
The findings indicate that Cav1.3 (α1D) is connected to the Usher protein network. This conclusion leads to the hypothesis that, in the retina, whirlin scaffolds Cav1.3 (α1D) and therefore contributes to the organization of calcium channels in the photoreceptor cells, where both proteins may be involved in membrane fusions.
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