Moleclar Pathogenesis of Retinitis Pigmentosa Type 3

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DESCRIPTION (provided by applicant): Retinitis pigmentosa (RP) is a genetically and clinically heterogeneous retinal disease leading to photoreceptor cell death and ultimately, complete blindness. Yet, the molecular pathogenesis of most forms of inherited retinal degeneration remains until this date elusive. X-linked retinitis pigmentosa (XIRP) accounts for up to 33 percent of all forms of RP. The X-linked disorder, retinitis pigmentosa type 3, is responsible for about 75 percent of X-linked RP, 11 percent of all RP forms and it is considered to be the most severe form of RP. Recently, the genetic lesions leading to RP3 have been molecularly defined. They are caused by mutations in the so-called retinitis pigmentosa GTPase regulator (RPGR) gene in light of its homology to RCC1, a nucleotide-exchange factor for RanGTPase. All RP3-missense mutations to date identified are located in the RCC1-homologous domain. This gene is ubiquitously expressed but mutations in RPGR lead only to a visual phenotype primarily restricted to the retina. We have identified several retinal RPGR-interacting protein isoforms derived from the same gene that interact with RPGR in vitro and in vivo and these interactions are abrogated by human RP3-disease associated missense mutations. RPGR and its novel retinal substrate isoform(s) colocalize in the outer segments of rod photoreceptors. Thus, the novel RPGR substrates were designated RPGR interacting proteins (RPGRIPs). Also, the human RPGRIP gene colocalizes with RP16 locus. RPGRIPs contain very long, variable coiled-coil domains with homology to proteins involved in vesicular trafficking and a conserved, globular and C-terminal RPGR-interacting domain, suggesting that these proteins mediate vesicular-transport associated processes. The goals of this proposal are to understand the molecular pathogenesis of XIRP3, in particular, the molecular basis of the retina specific effects of RPGR mutations leading to RP3 and the biological role of the novel RPGRIPs.