Loss of REP1 impacts choroidal melanogenesis in choroideremia

Abstract

AbstractChoroideremia (CHM) is a rare X-linked chorioretinal dystrophy affecting the photoreceptors, retinal pigment epithelium (RPE) and choroid, however, the involvement of the choroid in disease progression is not fully understood. CHM is caused by mutations in theCHMgene, encoding the ubiquitously expressed Rab escort protein 1 (REP1). REP1 plays an important role in intracellular trafficking of vesicles, including melanosomes. In this study, we examined ultrastructure of the choroid inchmru848fish andChmnull/WTmouse models using transmission electron microscopy. Significant pigmentary disruptions were observed, with a lack of melanosomes in the choroid ofchmru848fish from 4 days post fertilisation (4dpf). Total melanin and expression of melanogenesis genestyr,tryp1a,mitf, dctandpmelwere also reduced from 4dpf. InChmnull/WTmice, choroidal melanosomes were significantly smaller at 1 month and at 1 year, eumelanin was reduced, and the choroid was thicker. The choroid in CHM patients was also examined using optical coherence tomography (OCT) and OCT- angiography (OCT-A) and the area of preserved choriocapillaris (CC) was found to be smaller than that of overlying photoreceptors, indicating that the choroid is degenerating at a faster rate. Histopathology of an enucleated eye from a 74-year-old CHM male patient revealed isolated areas of RPE but no associated underlying CC. Significant degenerative changes in the choroid of CHM patients and animal models are seen, highlighting the importance of administrative routes involving the choroid, such as suprachoroidal delivery. Pigmentary disruptions in CHM animal models reveal an important role for REP1 in melanogenesis, and drugs that improve melanin production represent a potential novel therapeutic avenue.