Rpgr, short for Retinitis Pigmentosa GTPase Regulator, is a gene playing a crucial role in photoreceptor physiology. Mutations in this gene are the predominant cause of X-linked retinitis pigmentosa (XLRP) and a common cause of cone-rod dystrophy (CORD) [1]. It is located in photoreceptor connecting cilia and likely plays a role in the function of the ciliary gate, which controls access of both membrane and soluble proteins to the photoreceptor outer segment [2]. Rpgr is also a guanine nucleotide exchange factor that activates the small GTPase RAB37, and this activation is required for retinal function via autophagy regulation [3].

Rpgr knockout (KO) in mice leads to photoreceptor degeneration due to autophagy impairment in the retina [3]. The retinopathy phenotypes of Rpgr KO retinas can be rescued by the adeno-associated virus-mediated transfer of pre-trans-splicing molecules, which produce normal Rpgr mRNAs via trans-splicing in the Rpgr KO retinas, thus upregulating autophagy and reverting retinal homeostasis to normal [3].

In conclusion, Rpgr is essential for maintaining normal retinal function, especially in photoreceptor cells. The Rpgr KO mouse model has been instrumental in revealing its role in autophagy regulation in the retina, providing insights into the pathogenesis of XLRP and related retinal dystrophies, and potentially guiding the development of gene-replacement therapies [1,2,3].

References:

1. Awadh Hashem, Shaima, Georgiou, Michalis, Ali, Robin R, Michaelides, Michel. 2023. RPGR-Related Retinopathy: Clinical Features, Molecular Genetics, and Gene Replacement Therapy. In Cold Spring Harbor perspectives in medicine, 13, . doi:10.1101/cshperspect.a041280. https://pubmed.ncbi.nlm.nih.gov/37188525/

2. Megaw, Roly D, Soares, Dinesh C, Wright, Alan F. 2015. RPGR: Its role in photoreceptor physiology, human disease, and future therapies. In Experimental eye research, 138, 32-41. doi:10.1016/j.exer.2015.06.007. https://pubmed.ncbi.nlm.nih.gov/26093275/

3. Ying, Ruhong, Li, Cong, Li, Huirong, Cheng, Hanhua, Zhou, Rongjia. 2024. RPGR is a guanine nucleotide exchange factor for the small GTPase RAB37 required for retinal function via autophagy regulation. In Cell reports, 43, 114010. doi:10.1016/j.celrep.2024.114010. https://pubmed.ncbi.nlm.nih.gov/38536817/