REP1-deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Choroideremia (CHM) is a X-linked recessive chorioretinal dystrophy caused by mutations in CHM, encoding for Rab escort protein 1 (REP1). Loss of functional REP1 leads to the accumulation of unprenylated Rab proteins and defective intracellular protein trafficking, the putative cause for photoreceptor, retinal pigment epithelium (RPE) and choroidal degeneration. CHM is ubiquitously expressed, but adequate prenylation is considered to be achieved, outside the retina, through the isoform REP2. Recently, the possibility of systemic features in CHM has been debated, hence, in this study whole metabolomic analysis of plasma samples from 25 CHM patients versus age and gender matched controls was performed. Results showed plasma alterations in oxidative stress-related metabolites, coupled with alterations in tryptophan metabolism leading to significantly raised serotonin levels. Lipid metabolism was disrupted with decreased branched fatty acids and acylcarnitines, suggestive of dysfunctional lipid oxidation, and imbalances of several sphingolipids and glycerophospholipids. Targeted lipidomics of the chmru848 zebrafish provided further evidence for dysfunction, with the use of Fenofibrates over Simvastatin circumventing the prenylation pathway to improve the lipid profile and increase survival. This study provides strong evidence for systemic manifestations of CHM and proposes novel pathomechanisms and targets for therapeutic consideration.
Date Issued
2021-05-10
Date Acceptance
2021-03-01
Citation
JCI Insight, 2021, 6 (9)
ISSN
2379-3708
Publisher
American Society for Clinical Investigation
Journal / Book Title
JCI Insight
Volume
6
Issue
9
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33755601
PII: 146934
Subjects
Genetic diseases
Metabolism
Ophthalmology
Publication Status
Published
Coverage Spatial
United States
Article Number
ARTN e146934
Date Publish Online
2021-03-23