# The molecular mechanism responsible for HbSC retinopathy may depend on the action of the angiogenesis-related genes ROBO1 and SLC38A5

## TL;DR

This study explores how genes ROBO1 and SLC38A5 may contribute to retinopathy in HbSC disease, a type of sickle cell disease that affects vision.

## Contribution

The study identifies ROBO1 and SLC38A5 as key genes involved in the molecular mechanism of proliferative sickle cell retinopathy.

## Key findings

- ROBO1 and SLC38A5 are significantly up-regulated in patients with proliferative sickle cell retinopathy.
- ROBO1 promotes endothelial cell migration and retinal angiogenesis, while SLC38A5 regulates amino acid uptake for endothelial cell proliferation.
- The findings provide insights into the molecular pathophysiology of proliferative sickle cell retinopathy.

## Abstract

HbSC disease, a less severe form of sickle cell disease, affects the retina more frequently and patients have higher rates of proliferative retinopathy that can progress to vision loss. This study aimed to identify differences in the expression of endothelial cell-derived molecules associated with the pathophysiology of proliferative sickle cell retinopathy (PSCR). RNAseq was used to compare the gene expression profile of circulating endothelial colony-forming cells from patients with SC hemoglobinopathy and proliferative retinopathy (n = 5), versus SC patients without retinopathy (n = 3). Real-time polymerase chain reaction (qRT-PCR) was used to validate the RNAseq results. A total of 134 differentially expressed genes (DEGs) were found. DEGs were mainly associated with vasodilatation, type I interferon signaling, innate immunity and angiogenesis. Among the DEGs identified, we highlight the most up-regulated genes ROBO1 (log2FoldChange = 4.32, FDR = 1.35E-11) and SLC38A5 (log2FoldChange = 3.36 FDR = 1.59E-07). ROBO1, an axon-guided receptor, promotes endothelial cell migration and contributes to the development of retinal angiogenesis and pathological ocular neovascularization. Endothelial SLC38A5, an amino acid (AA) transporter, regulates developmental and pathological retinal angiogenesis by controlling the uptake of AA nutrient, which may serve as metabolic fuel for the proliferation of endothelial cells (ECs) and consequent promotion of angiogenesis. Our data provide an important step towards elucidating the molecular pathophysiology of PSCR that may explain the differences in ocular manifestations between individuals with hemoglobinopathies and afford insights for new alternative strategies to inhibit pathological angiogenesis.