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Human Molecular Genetics Advance Access originally published online on November 21, 2005
Human Molecular Genetics 2005 14(24):3933-3943; doi:10.1093/hmg/ddi417
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2

Jan Reiners1,{dagger}, Erwin van Wijk2,{dagger}, Tina Märker1, Ulrike Zimmermann5, Karin Jürgens1, Heleen te Brinke2, Nora Overlack1, Ronald Roepman3,4, Marlies Knipper5, Hannie Kremer2 and Uwe Wolfrum1,*

1Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, D-55099 Mainz, Germany, 2Department of Otorhinolaryngology, 3Department of Human Genetics and Centre for Molecular and 4Nijmegan Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands and 5Department of Otorhinolaryngology, Hearing Research Centre Tübingen, THRC, Molecular Neurobiology, University of Tübingen, Germany

* To whom correspondence should be addressed. Tel: +49 61313925148; Fax: +49 61313923815; Email: wolfrum{at}uni-mainz.de

Received August 19, 2005; Revised October 26, 2005; Accepted November 2, 2005

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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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