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Human Molecular Genetics Advance Access originally published online on January 24, 2006
Human Molecular Genetics 2006 15(5):751-765; doi:10.1093/hmg/ddi490
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1

Erwin van Wijk1, Bert van der Zwaag4, Theo Peters1, Ulrike Zimmermann5, Heleen te Brinke1, Ferry F.J. Kersten1, Tina Märker6, Elena Aller7,8, Lies H. Hoefsloot2, Cor W.R.J. Cremers1, Frans P.M. Cremers2,3, Uwe Wolfrum6, Marlies Knipper5, Ronald Roepman2,3,{dagger} and Hannie Kremer1,*,{dagger}

1Department of Otorhinolaryngology, 2Department of Human Genetics, Radboud University Nijmegen Medical Centre, 3Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands, 4Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands, 5Department of Otorhinolaryngology, Hearing Research Centre Tübingen, THRC, Molecular Neurobiology, University of Tübingen, Tübingen, Germany, 6Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany and 7Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario La Fe and 8Departamento de Genética, Universidad de Valencia, Valencia, Spain

* To whom correspondence should be addressed at: Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Internal Postal Code 377, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 243610487; Fax: +31 243668752; Email: h.kremer{at}antrg.umcn.nl

Received November 17, 2005; Accepted January 18, 2006

Mutations in the DFNB31 gene encoding the PDZ scaffold protein whirlin are causative for hearing loss in man and mouse. Whirlin is known to be essential for the elongation process of the stereocilia of sensory hair cells in the inner ear, though its complete spatial and temporal expression patterns remained elusive. Here, we demonstrate that, in embryonic development, the gene is not only expressed in the inner ear, but also in the developing brain and the retina. Various isoforms of whirlin are widely and differentially expressed, and we provide evidence that whirlin directly associates with USH2A isoform b and VLGR1b, two proteins that we previously reported to be part of the Usher protein interactome. These proteins co-localize with whirlin at the synaptic regions of both photoreceptor cells and outer hair cells in the cochlea. These findings indicate that whirlin is part of a macromolecular PDZ protein scaffold that functions in the organization of the pre- and/or postsynaptic side of photoreceptor and hair cell synapses. Whirlin might be involved in synaptic adhesion through interaction with USH2A and VLGR1b as well as in synaptic development as suggested by its spatial and temporal expression patterns. In addition, we demonstrate that whirlin, USH2A and Vlgr1b co-localize at the connecting cilium and the outer limiting membrane of photoreceptor cells and in spiral ganglion neurons of the inner ear. Our data show that whirlin is connected to the dynamic Usher protein interactome and indicate that whirlin has a pleiotropic function in both the retina and the inner ear.

{dagger} The authors contributed equally to this work.


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