RPGR Gene: Function, Mutations, and Associated Diseases | Biomedical Resource

The RPGR (Retinitis Pigmentosa GTPase Regulator) gene is located on the X chromosome at Xp11.4 and encodes a protein that plays a critical role in the structure and function of cilia, particularly in photoreceptor cells of the retina. The gene undergoes complex alternative splicing, producing multiple isoforms, including a major isoform (RPGR-ORF15) that is highly expressed in the retina. Mutations in RPGR are a leading cause of X-linked retinitis pigmentosa (XLRP) and can also cause cone-rod dystrophy and other ciliopathies. The protein localizes to the connecting cilium of photoreceptors and interacts with other ciliary proteins to regulate protein transport and maintain photoreceptor integrity. RPGR is also expressed in other ciliated tissues, and its dysfunction can lead to extraocular manifestations in some patients. This gene is essential for vision, and its mutations are a major target for gene therapy research.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Ciliary transport pathway

• Photoreceptor cell maintenance

• Intraflagellar transport (IFT) - RPGR interacts with IFT proteins

• Retinal degeneration pathways (e.g.

• apoptosis in photoreceptors)

The RPGR protein is a 90-120 kDa protein (depending on isoform) that localizes to the connecting cilium of photoreceptors and to cilia in other cell types. It contains an RCC1-like domain (RLD) that has guanine nucleotide exchange factor (GEF) activity for small GTPases, though its exact enzymatic function is still under investigation. The protein interacts with several ciliary proteins, including RPGRIP1, RPGRIP1L, and nephrocystin, and is involved in regulating protein trafficking along the cilium. The major retinal isoform, RPGR-ORF15, contains a repetitive glycine-rich domain encoded by exon ORF15, which is essential for photoreceptor function. Mutations in this domain are the most common cause of XLRP. RPGR is also involved in maintaining the structural integrity of the connecting cilium and in the transport of phototransduction components. In non-retinal tissues, RPGR is important for ciliary function in respiratory epithelium and sperm flagella, explaining some extraocular phenotypes.