Authors: Roepman, Ronald; Bernoud-Hubac, Nathalie¹; Schick, Diana E.¹; Maugeri, Alessandra; Berger, Wolfgang²; Ropers, Hans-Hilger²; Cremers, Frans P.M.; Ferreira, PauloA.¹

Source: Human Molecular Genetics, Volume 9, Number 14, 1 September 2000 , pp. 2095-2105(11)

Publisher: Oxford University Press

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 ofRPGRIP1 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.

Document Type: Research article

Affiliations: 1: Pharmacology and Toxicology Department, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53151, USA and 2: Max-Planck-Institut für Molekulare Genetik, Ihnestrasse 73, 14195 Berlin, Germany

Publication date: 2000-09-01

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• Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics.

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• By this author: Roepman, Ronald ;  Bernoud-Hubac, Nathalie ;  Schick, Diana E. ;  Maugeri, Alessandra ;  Berger, Wolfgang ;  Ropers, Hans-Hilger ;  Cremers, Frans P.M. ;  Ferreira, PauloA.

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