A defect in retinitis pigmentosa (RP) GTPase regulator (RPGR) causes X-linked RP, one of the most common and severe forms of inherited retinal degeneration. Progress towards understanding the RPGR function and disease mechanism is stymied by a lack of knowledge as to what constitutes the primary structure of a functional RPGR, due to the exceptional heterogeneity of RPGR transcript splicing which we document in Preliminary Studies in the current proposal. Our central hypothesis is that the N-terminal half of RPGR sequence encompassing the RCC1 homology domain constitutes the core functional module of RPGR. Functional constraint on the remainder of the primary sequence, with the exception of a highly conserved C-terminal tail, may be relaxed. This proposal will critically evaluate this hypothesis and will attempt to define the minimal RPGR primary structure sufficient for function, as defined by the ability to rescue the RPGR null phenotype. These studies are potentially of high impact as they will serve as the basis on which further studies may be carried out to determine RPGR function at the molecular level and to elucidate the pathogenic mechanism of RPGR mutations.
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