Over 200 different RPGR mutations have so far been reported in patients with X-linked retinopathies of diverse clinical phenotypes. A vast majority of these are nonsense mutations or deletions/insertions resulting in frameshift, which are predicted to cause premature truncation of the RPGRORF15 protein. While mutations in the ORF15 exon are generally associated with a milder disease, mutations in RPGR exons 1–14 result in a more severe disease. Initially, most human RPGR mutations were hypothesized to have a null phenotype in males; however, wide variations in clinical phenotype of males and carrier females, and complexities associated with RPGR transcripts and protein isoforms strongly indicate that several disease alleles may in fact be hypomorphs (with partial function).
What is the role of RPGR as part of distinct multiprotein complexes at the cilium and how do mutations in RPGR cause photoreceptor degeneration? Though basic components associated with ciliary transport have been discovered (Rosenbaum et al. 1999
; Rosenbaum 2002
), the mechanisms of cargo sorting and assembly of protein complexes, and their regulation by signalling pathways in photoreceptors have not been elucidated. Periodic turnover of photoreceptor outer segments demands efficient functioning of the ciliary transport process (Besharse et al. 2003
). We hypothesize that RPGR facilitates the assembly of transport protein complexes by interacting with distinct ciliary—basal body— centrosome (CBC) proteins, and that RPGR’s localization in the photoreceptor cilia is necessary for efficient intersegmental transport ().
Figure 3 Schematic representation of the RPGR and ciliarybasal bodycentrosomal (CBC) protein complexes in photoreceptors; binary interactions and macromolecular protein complexes facilitate microtubule-based ciliary transport. Dashed lines indicate interactions (more ...)
Owing to the associated clinical heterogeneity, a detailed genotype–phenotype correlation analysis is critical to understand the progression and pathogenesis of RPGR-associated disease. These studies will benefit from characterization of additional animal model systems representing RPGR mutations as well as identification of components of the RPGR-interactome in photoreceptors. For example, characterization of photoreceptor dysfunction and degeneration in knock-in mouse mutants of Rpgr can assist in understanding associated disease pathogenesis. In addition, functional analysis of the disease-causing mutations of RPGR, such as the effect on RPGR localization, integrity of the interactome and effect on cilia-dependent development are required to delineate the mechanism of heterogenic phenotype observed in patients. These investigations should assist in designing rational therapeutic paradigms for XLRP as well as associated ciliary disorders.