Another step towards the understanding of the pathogenesis underlying Usher syndrome type 2.
The molecular mechanisms of retinal degeneration due to compromised formation and function of the USH2-associated protein complex remain elusive. In a recent publication, researchers joining in the Radboud Zebrafish Facility took another step to unravel this pathogenic mechanism. They have isolated and characterized whirlin-associated protein complexes from zebrafish photoreceptor cells. They generated transgenic zebrafish that express Strep/FLAG-tagged Whrna, a zebrafish ortholog of human whirlin, under the control of a photoreceptor-specific promoter.
The generation of an in vivo tissue specific SF-Whrna overexpression model led to unique insights into the potential role of whirlin in the organization and/or function of the synapse. The association of whirlin with postsynaptic density proteins we identified was neither detected by GST pull-down assay or a previous large ciliary proteomics study. The novel in vivo affinity purification approach presented in the publication thus identified presumably relevant Whrna-associated proteins and provided new insights into the role of whirlin. Future functional analyses using suitable cellular and animal models will reveal the biological relevance of the identified interactions in the retina and to what extent a disrupted association with those proteins might contribute to the observed retinal phenotype in USH2d patients.