# Genetic Analysis of Choroideremia-Related Rab Escort Proteins

## TL;DR

This study explores how mutations in Rab escort proteins cause choroideremia, a rare eye disease, and reveals early systemic effects before vision loss occurs.

## Contribution

The study identifies systemic metabolic and inflammatory changes in REP-1-deficient mice preceding retinal degeneration and reveals lethal effects of dual REP deficiency.

## Key findings

- REP-1 deficiency in mice causes metabolic and inflammatory changes before retinal degeneration.
- Transcriptomic analysis shows proinflammatory signaling in REP-1-deficient retinas.
- Dual deficiency in REP-1 and REP-2 leads to lethality in mice and cell cultures.

## Abstract

Choroideremia is a rare X-linked recessive retinal disorder characterized by progressive vision loss caused by retinal degeneration resulting from mutations in the CHM gene, which encodes Rab escort protein 1 (REP-1). In humans and mice, the Rab escort protein (REP) family consists of two members, REP-1 and REP-2, with REP-2 hypothesized to compensate for REP-1 deficiency in tissues outside the eye in choroideremia. In this study, we conducted a systematic mutational analysis of the mouse orthologs of REP-1 and REP-2. Blood analyses revealed metabolic abnormalities in the mutant mice deficient for REP-1, resembling the systemic metabolic disturbances observed in individuals with choroideremia, such as altered lipid and hemoglobin metabolism. We also observed an elevation in systemic inflammatory biomarkers in these mutant mice. Interestingly, these systemic abnormalities emerged before retinal degeneration became detectable in REP-1-deficient mice. Transcriptomic analysis of retinas isolated from REP-1 deficient mice revealed enrichment of proinflammatory signaling pathways. These results suggest important similarities between choroideremia and some forms of retinitis pigmentosa. While engineered loss of REP-2 alone caused no detectable phenotypic changes, dual deficiency in REP-1 and REP-2 resulted in lethality under both in vivo and in vitro conditions. Our findings offer novel insights into REPs and deepen our understanding of choroideremia, which may contribute to the development of new treatments for this genetic condition.