Introduction:Pathogenic mutations inRPGRORF15, one of two major humanRPGRisoforms, were responsible for most X-linked retinitis pigmentosa cases. Previous studies have shown thatRPGRplays a critical role in ciliary protein transport. However, the precise mechanisms of disease triggered byRPGRORF15mutations have yet to be clearly defined. There are two homologous genes in zebrafish,rpgraandrpgrb. Zebrafishrpgrahas a single transcript homologous to humanRPGRORF15;rpgrbhas two major transcripts:rpgrbex1-17andrpgrbORF15, similar to humanRPGRex1-19andRPGRORF15, respectively.rpgrbknockdown in zebrafish resulted in both abnormal development and increased cell death in the dysplastic retina. However, the impact of knocking downrpgrain zebrafish remains undetermined. Here, we constructed arpgramutant zebrafish model to investigate the retina defect and related molecular mechanism.Methods:we utilized transcription activator-like effector nuclease (TALEN) to generate arpgramutant zebrafish. Western blot was used to determine protein expression. RT-PCR was used to quantify gene transcription levels. The visual function of embryonic zebrafish was detected by electroretinography. Immunohistochemistry was used to observe the pathological changes in the retina of mutant zebrafish and transmission electron microscope was employed to view subcellular structure of photoreceptor cells.Results:A homozygousrpgramutant zebrafish with c.1675_1678delins21 mutation was successfully constructed. Despite the normal morphological development of the retina at 5 days post-fertilization, visual dysfunction was observed in the mutant zebrafish. Further histological and immunofluorescence assays indicated thatrpgramutant zebrafish retina photoreceptors progressively began to degenerate at 3-6 months. Additionally, the mislocalization of cone outer segment proteins (Opn1lw and Gnb3) and the accumulation of vacuole-like structures around the connecting cilium below the OSs were observed in mutant zebrafish. Furthermore, Rab8a, a key regulator of opsin-carrier vesicle trafficking, exhibited decreased expression and evident mislocalization in mutant zebrafish.Discussion:This study generated a novelrpgramutant zebrafish model, which showed retinal degeneration. our data suggested Rpgra is necessary for the ciliary transport of cone-associated proteins, and further investigation is required to determine its function in rods. Therpgramutant zebrafish constructed in this study may help us gain a better understanding of the molecular mechanism of retinal degeneration caused byRPGRORF15mutation and find some useful treatment in the future.