Abstract
Choroideremia is a progressive X-linked chorioretinal degeneration, caused by mutations in the CHM gene. CHM encodes REP1 protein, which regulates intracellular trafficking via Rab proteins. The pathogenic mechanism of choroideremia is not fully characterised yet. We generated iPSC-RPE from WT and CHMY42X patient-derived fibroblast lines. Samples were sent off for bulk RNA sequencing. Differential gene expression and enrichment analysis were performed (threshold cut off for the adjusted p value of < 0.05). CHMY42X and WT patient-derived fibroblasts were sent for proteomic analysis after incubation with S-geranylgeranylation probes. In CHMY42X iPSC-RPE, 4210 genes were significantly up-regulated, and 4501 genes were significantly down-regulated. Upregulation of inflammatory, oxidative stress and senescence gene pathways were observed. RAB gene expression was widely dysregulated. In CHMY42X fibroblasts, Rabs involved in melanogenesis and senescence control were under-prenylated. Overall, our work shows CHMY42X iPSC-RPE and CHMY42X fibroblasts are in a pro-senescent state, with disrupted melanogenesis. Identifying common underlying mechanisms of retinal disease paves the way for more accessible patient treatments.
