Serum Biomarkers and Trafficking Defects in Peripheral Tissues Reflect the Severity of Retinopathy in Three Brothers Affected by Choroideremia

Abstract

Choroideremia (CHM) is an X-linked form of retinal degeneration, caused by loss of function mutations in the CHM gene that encodes Rab Escort Protein 1 gene (REP1). REP1 is a key regulator of vesicular trafficking, phagosome fusion, and maturation. We investigated the effects of different CHM mutations in monocytes derived from CHM patients. Phagocytosis in monocytes was tracked with a pH-dependent dye conjugated with E. coli, and the rate of degradation of engulfed material was determined using labeled DQTM-Ovalbumin (Molecular Probes, Eugene, OR). Monocytes (CD14+ fraction) from 6 age-matched controls and 3 CHM patients (brothers) with the same mutation in CHM were compared for different aspects of intracellular vesicle transport. The three brothers demonstrated a large degree of variability in trafficking defects and serum levels of PEDF, VEGF, and MCP1 factors, which correlated with the clinical severity of their disease. We demonstrated that peripheral cells from CHM patients have characteristic defects that have not previously been recognized and could be used as alternative models to study the cellular effects of different mutations in the CHM gene and the mechanisms surrounding the progressive retinal degeneration in this condition.