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

2008; Oxford University Press; Volume: 18; Issue: 1 Linguagem: Inglês

10.1093/hmg/ddn312

1460-2083

Erwin van Wijk, Ferry F.J. Kersten, Aileen Kartono, Dorus A. Mans, Kim Brandwijk, Stef J.F. Letteboer, Theo Peters, Tina Märker, Xiumin Yan, Cor W. R. J. Cremers, Frans P.M. Cremers, Uwe Wolfrum, Ronald Roepman, Hannie Kremer,

Microtubule and mitosis dynamics

Usher syndrome (USH) and Leber congenital amaurosis (LCA) are autosomal recessive disorders resulting in syndromic and non-syndromic forms of blindness.In order to gain insight into the pathogenic mechanisms underlying retinal degeneration, we searched for interacting proteins of USH2A isoform B (USH2A isoB ) and the LCA5-encoded protein lebercilin.We identified a novel isoform of the centrosomal ninein-like protein, hereby named Nlp isoform B (Nlp isoB ), 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 USH2A isoB did not depend on this.Upon expression in ARPE-19 cells, recombinant Nlp isoB , lebercilin and USH2A isoB were all found to co-localize 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 Nlp isoB with USH2A isoB and lebercilin indicates that Nlp can be considered as a novel candidate gene for USH, LCA and allied retinal ciliopathies.