Abstract
Abstract: :
Purpose: Genetic lesions in RPGR lead to a host of heterogeneous and severe retinal dystrophies. To elucidate the molecular pathogenesis of mutations in RPGR, we previously identified several retinal RPGR–interacting protein substrates, RPGRIP1s, in the human and the bovine that are derived by complex alternative splicing and limited proteolysis. Mutations in RPGRIP1 lead to Leber congenital amaurosis, a retinopathy with a broader expressivity than those cause by mutations in RPGR. This likely reflects the expression of RPGRIP1 in photoreceptors and selective inner retinal neurons. RPGRIP1s are comprised of at least three distinct structural domains: the variable N–terminal coiled–coil structural maintenance chromosome (SMC) and central C2 domains, and the conserved C–terminal RPGR–interacting domain (RID). In an attempt to elucidate the pathogenesis of X–linked RP3 (and allied dystrophies) and Leber Congenital Amaurosis, the goal of this work was to identify unique functional properties among the RPGRIP1 isoforms and the role of RPGR on the function of these. Methods: A combination of RT–PCR, cell–based assays and molecular metodologies were employed to characterize RPGRIP1s and the functional dependence of these on RPGR isoforms. Results: We have identified a novel RPGRIP1 isoform conserved in the human and the mouse. This isoform is expressed in the retina and across other tissues. However, the abundance of the novel RPGRIP1 isoform is, respectively, much higher and lower in the mouse and the human among all other RPGRIP1 isoforms examined. More importantly, this isoform stands out among other RPGRIP1 isoforms in light of its RPGR–independent function. Conclusions: The large diversity and distinct expression profiles of RPGRIP1 isoforms and selective dependence of these on RPGR function likely account for distinct roles of RPGRIP1s among retinal neurons and/or subcompartments thereof. In addition, this may contribute to the heterogeneous and/or disparity phenotypes linked to genetic lesions in RPGRIP1 and RPGR.
Keywords: retinal degenerations: hereditary • gene/expression • retinal degenerations: cell biology