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Human Molecular Genetics Advance Access published online on September 30, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn312
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein

Erwin van Wijk1,2,7, Ferry F.J. Kersten1,2,3,4,7, Aileen Kartono2,4, Dorus A. Mans2, Kim Brandwijk2, Stef J.F. Letteboer2, Theo A. Peters1,7, Tina Märker5, Xiumin Yan6, Cor W.R.J. Cremers1,7, Frans P.M. Cremers2,4, Uwe Wolfrum5, Ronald Roepman2,4,* and Hannie Kremer1,4,7,*,{Psi}

1 Departments of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 2 Departments of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 3 Departments of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 4 Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands 5 Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University of Mainz, Mainz, Germany 6 Department of Cell Biology, Max-Planck Institute of Biochemistry, Martinsried, Germany 7 Donders Centre for Neuroscience, Nijmegen, The Netherlands

{Psi} Corresponding author: Hannie Kremer, Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, internal postal code 377, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31.24.3610487; Fax.: +31.24.3668752. Email: h.kremer{at}antrg.umcn.nl

Received May 16, 2008; Revised September 1, 2008; Accepted September 25, 2008

Usher syndrome (USH) and Leber congenital amaurosis (LCA) are autosomal recessive disorders resulting in syndromic and nonsyndromic forms of blindness. In order to gain insight into the pathogenic mechanisms underlying retinal degeneration, we searched for interacting proteins of USH2A isoform B (USH2AisoB) and the LCA5-encoded protein lebercilin. We identified a novel isoform of the centrosomal ninein-like protein, hereby named Nlp isoform B (NlpisoB), as a common interactor. Although we identified the capacity of this protein to bind calcium with one of its three EF hand domains, the interacton with USH2AisoB did not depend on this. Upon expression in ARPE-19 cells, recombinant NlpisoB, lebercilin, and USH2AisoB were all found to colocalize at the centrosomes. Staining of retinal sections with specific antibodies against all three proteins revealed their co-localization at the basal bodies of the photoreceptor connecting cilia. Based on this subcellular localization and the nature of their previously identified binding partners, we hypothesize that the pathogenic mechanisms for LCA and USH show significant overlap and involve defects in ciliogenesis, cilia maintenance, and intraflagellar and/or microtubule-based transport. The direct association of NlpisoB with USH2AisoB and lebercilin indicates that Nlp can be considered as a novel candidate gene for USH, LCA and allied retinal ciliopathies.

* Both authors contributed equally to this work


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