RPGRIP1s with distinct neuronal localization and biochemical properties associate selectively with RanBP2 in amacrine neurons - PubMed (original) (raw)

Comparative Study

. 2003 Aug 1;12(15):1847-63.

doi: 10.1093/hmg/ddg202.

Affiliations

Comparative Study

RPGRIP1s with distinct neuronal localization and biochemical properties associate selectively with RanBP2 in amacrine neurons

P Castagnet et al. Hum Mol Genet. 2003.

Abstract

RPGR and RPGRIP1 are molecular partners with vital roles in retinal function. Mutations in RPGR are implicated in heterogeneous retinal phenotypes, while those in RPGRIP1 lead to Leber congenital amaurosis. RPGR and RPGRIP1s differentially localize in photoreceptors among species. This may contribute to phenotype disparities among species bearing mutations in RPGR. However, it cannot account for the phenotype heterogeneity associated with RPGR- and RPGRIP1-linked mutations in the human. The existence of RPGRIP1 isoforms with distinct cellular, subcellular localizations and biochemical properties in the retina is shown. High mass RPGRIP1 isoforms, p175/p150, enriched in the outer segment (OS) compartment of photoreceptors are identified. The remaining isoforms are present across subcellular fractions, including nuclei and are soluble. The p175/p150 are predominantly sequestered in the cytoskeleton-insoluble fraction of OS and nuclei. In selective amacrine cells, and in the transformed photoreceptor line, 661W, RPGRIP1s localize at restricted foci to nuclear pore complexes and/or the vicinity of these. Among the nucleoporins, RPGRIP1 isoforms selectively associate in vivo with RanBP2 (Nup358). RPGRIP1s also decorate microtubules in 661W cells and occasionally form coiled-like inclusion bodies in the perikarya. These results support distinct but complementary functions of RPGRIP1 isoforms in cytoskeletal-mediated processes in photoreceptors and amacrine neurons, and may explain the Leber phenotype linked to RPGRIP1 mutations in humans. Moreover, the data implicate a role of RanBP2 in the pathogenesis of neuro(retino)pathies and as a docking station to mediate the nucleocytoplasmic shuttling of RPGRIP1s and their interaction with other partners in amacrine and 661W neurons.

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