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Mutations in retinitis pigmentosa GTPase regulator ( RPGR ) cause severe retinal ciliopathy, X-linked retinitis pigmentosa. Although two major alternatively spliced isoforms, RPGR ex1-19  and RPGR ORF15 , are expressed, the relative importance of these isoforms in disease pathogenesis is unclear. Here, we analyzed fibroblast samples from eight patients and found that all of them form longer cilia than normal controls, albeit to different degrees. Although all mutant  RPGR ORF15   messenger RNAs (mRNAs) are unstable, their steady-state levels were similar or higher than those in the control cells, suggesting there may be increased transcription. Three of the fibroblasts that had higher levels of mutant  RPGR ORF15   mRNA also exhibited significantly higher levels of  RPGR ex1-19   mRNA. Four samples with unaltered  RPGR ex1-19   levels carried mutations in  RPGR ORF15   that resulted in this isoform being relatively less stable. Thus, in all cases, the  RPGR ex1-19  / RPGR ORF15   isoform ratio was increased, and this was highly correlative to the cilia extension defect. Moreover, overexpression of  RPGR ex1-19   (mimicking the increase in  RPGR ex1-19   to  RPGR ORF15   isoform ratio) or  RPGR ORF15   (mimicking reduction of the ratio) resulted in significantly longer or shorter cilia, respectively. Notably, the cilia length defect appears to be attributable to both the loss of the wild-type RPGR ORF15  protein and to the higher levels of the  RPGR ex1-19   isoform, indicating that the observed defect is due to the altered isoform ratios. These results suggest that maintaining the optimal  RPGR ex1-9   to  RPGR ORF15   ratio is critical for cilia growth and that designing strategies that focus on the best ways to restore the  RPGR ex1-19  / RPGR ORF15   ratio may lead to better therapeutic outcomes.

RPGR isoform imbalance causes ciliary defects due to exon ORF15 mutations in X-linked retinitis pigmentosa (XLRP)