Insights into X-linked retinitis pigmentosa type 3, allied diseases and underlying pathomechanisms.

In the past decade, we have witnessed great advances in the identification of genes underlying numerous neurodegenerative diseases and the stark complexity determining genotype-phenotype relationships that lead to the impairment, and ultimately, premature death of neurons. However, significant challenges lie ahead in understanding the pathobiological and spatiotemporal processes triggered by genetic lesions underlying neurodegenerative disorders. Neuroretinal dystrophies occupy a prominent place among neurodegenerative diseases, because of the large number and prevalence of disease-causing genes, the diverse functions, the wealth of allelic, non-allelic and clinical heterogeneities determining the phenotypic expressivity and penetrance of the disease and the ease of use of animal models to probe gene function and disease pathogenesis in a well-defined neuroretinal circuitry. Retinitis pigmentosa (RP) has a prevalence of about one in 4000. RP is a retinal dystrophy leading primarily to the progressive death of photon-capturing neurons--the rod photoreceptors. X-linked retinitis pigmentosa type 3 (XlRP3) accounts up to 14% of all RP cases, higher than any other single RP locus identified to date, and considered to be the most severe of all RP cases. The XlRP3 encodes the retinitis pigmentosa GTPase regulator (RPGR). RPGR interacts with the RPGR interacting protein-1 (RPGRIP1). Mutations in RPGRIP1 cause Leber's congenital amaurosis. This review highlights the progress devoted to understand the pathogenesis associated with XlRP3 and allied disorders and, concepts, trends and discrepancies emerging as molecular, subcellular and physiological processes linked to RPGR and RPGRIP1-protein network begin to be elucidated, and that may serve as a paradigm for other biological processes and neurodegenerative diseases.