Abstract
BackgroundChoroideremia (CHM) is a progressive X-linked retinopathy caused by mutations in the CHM gene, which encodes Rab escort protein-1 (REP-1), an escort protein involved in the prenylation of Rabs. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis and secretion in peripheral cells of CHM patients.Methodology/Principal FindingsTo evaluate this hypothesis, intracellular vesicle transport, lysosomal acidification and rates of proteolytic degradation were studied in monocytes (CD14+ fraction) and primary skin fibroblasts from the nine age-matched controls and thirteen CHM patients carrying 10 different loss-of-function mutations. With the use of pHrodo™ BioParticles® conjugated with E. coli, collagen I coated FluoSpheres beads and fluorescent DQ™ ovalbumin with BODYPY FL dye, we demonstrated for the first time that lysosomal pH was increased in monocytes of CHM patients and, as a consequence, the rates of proteolytic degradation were slowed. Microarray analysis of gene expression revealed that some genes involved in the immune response, small GTPase regulation, transcription, cell adhesion and the regulation of exocytosis were significantly up and down regulated in cells from CHM patients compared to controls. Finally, CHM fibroblasts secreted significantly lower levels of cytokine/growth factors such as macrophage chemoattractant protein-1 (MCP-1), pigment epithelial derived factor (PEDF), tumor necrosis factor (TNF) alpha, fibroblast growth factor (FGF) beta and interleukin (lL)-8.Conclusions/SignificanceWe demonstrated for the first time that peripheral cells of CHM patients had increased pH levels in lysosomes, reduced rates of proteolytic degradation and altered secretion of cytokines. Peripheral cells from CHM patients expose characteristics that were not previously recognized and could used as an alternative models to study the effects of different mutations in the REP-1 gene on mechanism of CHM development in human population.
Highlights
Choroideremia (CHM) is an X-linked monogenic disease caused by various mutations in the CHM gene that result in the loss of function of Rab GTPases (Rabs) escort protein (REP-1) and cause slow degeneration of the retinal pigment epithelium (RPE), choroid and photoreceptors
CHM is a monogenic disease caused by various mutations in the CHM gene that result in the loss of function of Rab escort protein (REP-1) and cause slow degeneration of RPE, choroid and photoreceptors
While many genetic studies have characterized the types of mutations in Rab escort protein-1 (REP-1) in CHM patients, few have added to our understanding of the pathogenesis of the disease
Summary
Choroideremia (CHM) is an X-linked monogenic disease caused by various mutations in the CHM gene that result in the loss of function of Rab escort protein (REP-1) and cause slow degeneration of the retinal pigment epithelium (RPE), choroid and photoreceptors. Mammals have a CHM gene and a CHM-like gene that encodes REP-2, which is thought to partially compensate for the lack of REP-1 in all tissues except the eye in CHM patients [10]. Choroideremia (CHM) is a progressive X-linked retinopathy caused by mutations in the CHM gene, which encodes Rab escort protein-1 (REP-1), an escort protein involved in the prenylation of Rabs. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis and secretion in peripheral cells of CHM patients
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