REP1 deficiency causes systemic dysfunction of lipid metabolism and oxidative stress in choroideremia

Abstract

Choroideremia (CHM) is an 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; therefore, in this study, whole metabolomic analysis of plasma samples from 25 CHM patients versus age- and sex-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, as well as imbalances of several sphingolipids and glycerophospholipids. Targeted lipidomics of the chm ru848 zebrafish provided further evidence for dysfunction, with the use of fenofibrate 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 potentially novel pathomechanisms and targets for therapeutic consideration.

Untargeted Metabolomics Reveals Lipid Impairment in the Liver of Adult Zebrafish (Danio rerio) Exposed to Carbendazim

“…Sphingolipids are a class of bioactive lipids that mediate physiologic and pathophysiologic processes and can have opposing effects; sphinganines are considered proapoptotic and can mediate apoptosis, growth arrest, and senescence. In contrast, sphingomyelin is linked to cell growth and adhesion (Adada et al, 2016; Cunha et al, 2021; García‐Arribas et al, 2016). Because sphingomyelins are synthesized by the transfer of phosphorylcholine from phosphatidylcholine to a ceramide in a reaction catalyzed by sphingomyelin synthase, the up‐regulation of N ‐arachidonoylsphinganine associated with the down‐regulation of sphingomyelin suggests compromised ceramide production in the ZT cluster.…”

Oxidative and Endoplasmic Reticulum Stress Represent Novel Therapeutic Targets for Choroideremia

“…In a whole-metabolomic screening of 25 CHM patients, the levels of cysteine were reduced; however, there was an accumulation of hypotaurine, which is indicative of oxidative stress. In addition, the levels of antioxidants were also significantly reduced in CHM patient plasma [ 7 ].…”

“…In most tissues except the retina, REP2, encoded by the CHM-like ( CHML ) gene, compensates for the lack of REP1, restricting pathogenesis to the eye. However, we recently carried out a whole-metabolomic screening of 25 patients and 25 age-matched controls and reported a range of altered metabolites in the CHM patient plasma, including those associated with oxidative stress; this indicates possible systemic manifestations, which may also be reflective of retinal status [ 7 ].…”

US Health Resource Utilization and Cost Burden Associated with Choroideremia

“…Additionally, whole metabolomic profiling of 25 individuals with choroideremia found altered lipid metabolism and increased oxidative stress, supporting the possibility of systemic effects of choroideremia, although further research is needed. 14 In published analyses, visual impairments, such as age-related macular degeneration (AMD), have also been associated with increased prevalence of chronic comorbidities. For example, cardiovascular and renal conditions were associated with an increased likelihood of early AMD in the US general population.…”