A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells

Hum Mol Genet. 2008 Jan 1;17(1):71-86. doi: 10.1093/hmg/ddm285. Epub 2007 Sep 28.


The human Usher syndrome (USH) is the most frequent cause of combined deaf-blindness. USH is genetically heterogeneous with at least 12 chromosomal loci assigned to three clinical types, USH1-3. Although these USH types exhibit similar phenotypes in human, the corresponding gene products belong to very different protein classes and families. The scaffold protein harmonin (USH1C) was shown to integrate all identified USH1 and USH2 molecules into protein networks. Here, we analyzed a protein network organized in the absence of harmonin by the scaffold proteins SANS (USH1G) and whirlin (USH2D). Immunoelectron microscopic analyses disclosed the colocalization of all network components in the apical inner segment collar and the ciliary apparatus of mammalian photoreceptor cells. In this complex, whirlin and SANS directly interact. Furthermore, SANS provides a linkage to the microtubule transport machinery, whereas whirlin may anchor USH2A isoform b and VLGR1b (very large G-protein coupled receptor 1b) via binding to their cytodomains at specific membrane domains. The long ectodomains of both transmembrane proteins extend into the gap between the adjacent membranes of the connecting cilium and the apical inner segment. Analyses of Vlgr1/del7TM mice revealed the ectodomain of VLGR1b as a component of fibrous links present in this gap. Comparative analyses of mouse and Xenopus photoreceptors demonstrated that this USH protein network is also part of the periciliary ridge complex in Xenopus. Since this structural specialization in amphibian photoreceptor cells defines a specialized membrane domain for docking and fusion of transport vesicles, we suggest a prominent role of the USH proteins in cargo shipment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • COS Cells
  • Cell Cycle Proteins
  • Chlorocebus aethiops
  • Cytoskeletal Proteins
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Humans
  • In Vitro Techniques
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Immunoelectron
  • Models, Biological
  • NIH 3T3 Cells
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Photoreceptor Cells, Vertebrate / metabolism*
  • Photoreceptor Cells, Vertebrate / ultrastructure
  • Protein Interaction Mapping
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Subcellular Fractions / metabolism
  • Transfection
  • Usher Syndromes / classification
  • Usher Syndromes / genetics*
  • Usher Syndromes / metabolism*
  • Xenopus / genetics
  • Xenopus / metabolism


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • Extracellular Matrix Proteins
  • Mass1 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, G-Protein-Coupled
  • Sans protein, mouse
  • USH1C protein, human
  • USH1G protein, human
  • USH2A protein, human
  • WHRN protein, human