title: Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2.
abstract: Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. USH is clinically and genetically heterogeneous with at least 11 chromosomal loci assigned to the three USH types (USH1A-G, USH2A-C, USH3A). Although the different USH types exhibit almost the same phenotype in human, the identified USH genes encode for proteins which belong to very different protein classes and families. We and others recently reported that the scaffold protein harmonin (USH1C-gene product) integrates all identified USH1 molecules in a USH1-protein network. Here, we investigated the relationship between the USH2 molecules and this USH1-protein network. We show a molecular interaction between the scaffold protein harmonin (USH1C) and the USH2A protein, VLGR1 (USH2C) and the candidate for USH2B, NBC3. We pinpoint these interactions to interactions between the PDZ1 domain of harmonin and the PDZ-binding motifs at the C-termini of the USH2 proteins and NBC3. We demonstrate that USH2A, VLGR1 and NBC3 are co-expressed with the USH1-protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. Our data indicate that the USH2 proteins and NBC3 are further partners in the supramolecular USH-protein network in the retina and inner ear which shed new light on the function of USH2 proteins and the entire USH-protein network. These findings provide first evidence for a molecular linkage between the pathophysiology in USH1 and USH2. The organization of USH molecules in a mutual 'interactome' related to the disease can explain the common phenotype in USH.
authors.affiliation: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Reiners
authors.forename: Erwin
authors.initials: E
authors.lastname: van Wijk
authors.forename: Tina
authors.initials: T
authors.lastname: Märker
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zimmermann
authors.forename: Karin
authors.initials: K
authors.lastname: Jürgens
authors.forename: Heleen
authors.initials: H
authors.lastname: te Brinke
authors.forename: Nora
authors.initials: N
authors.lastname: Overlack
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Marlies
authors.initials: M
authors.lastname: Knipper
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010786:Photoreceptor Cells / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics / Q000378:metabolism; D052245:Usher Syndromes / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D043562:Receptors, G-Protein-Coupled; D027982:Sodium-Bicarbonate Symporters; C485949:Adgrv1 protein, mouse; C498904:Slc4a7 protein, mouse; C492262:Ush1c protein, mouse; C492261:Ush1c protein, rat; C491810:Ush2a protein, mouse; C491809:Ush2a protein, rat