title: The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors.
abstract: Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene cause X-linked retinitis pigmentosa type 3 (RP3), a severe, progressive and degenerative retinal dystrophy eventually leading to complete blindness. RPGR is ubiquitously expressed, yet mutations in the RPGR gene lead to a retina-restricted phenotype. To date, all RP3 associated missense mutations that have been identified are located in the RCC1-homologous domain (RHD) of RPGR. To investigate the molecular pathogenesis of RP3, we screened retinal yeast two-hybrid libraries with the RHD of RPGR. We identified several alternatively spliced gene products, some with retina-restricted expression, that interact specifically with RPGR in vivo and in vitro. Thus, these proteins were named RPGR-interacting protein 1 (RPGRIP1) isoforms. They contain a C-terminal RPGR-interacting domain and stretches of variable coiled-coil domains homologous to proteins involved in vesicular trafficking. The interaction between RPGR and RPGRIP1 isoforms was impaired in vivo by RP3-associated mutations in RPGR. Moreover, RPGR and RPGRIP1 co-localize in the outer segment of rod photoreceptors, which is in full agreement with the retinitis pigmentosa phenotype observed in RP3 patients. The localization of RPGRIP1 at 14q11 makes it a strong candidate gene for RP16. These results provide a clue for the retina-specific pathogenesis in RP3, and hint towards the involvement of RPGR and RPGRIP1 in mediating vesicular transport-associated processes.
authors.affiliation: Department of Human Genetics, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Roepman
authors.forename: N
authors.initials: N
authors.lastname: Bernoud-Hubac
authors.forename: D E
authors.initials: DE
authors.lastname: Schick
authors.forename: A
authors.initials: A
authors.lastname: Maugeri
authors.forename: W
authors.initials: W
authors.lastname: Berger
authors.forename: H H
authors.initials: HH
authors.lastname: Ropers
authors.forename: F P
authors.initials: FP
authors.lastname: Cremers
authors.forename: P A
authors.initials: PA
authors.lastname: Ferreira
mesh_terms: D020413:3' Untranslated Regions; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002417:Cattle; D002474:Cell-Free System; D002883:Chromosomes, Human, Pair 14; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics*; D012160:Retina / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013696:Temperature; D014018:Tissue Distribution; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
chemical_list: D020413:3' Untranslated Regions; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D020033:Protein Isoforms; D011506:Proteins; C099929:RPGR protein, human; C415903:RPGRIP1 protein, human; D005982:Glutathione Transferase