July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Whole metabolomic profiling determines systemic dysfunction in Choroideremia
Author Affiliations & Notes
  • Mariya Moosajee
    Development, Ageing and Disease, UCL Institute of Ophthalmology, London, United Kingdom
    Genetics, Moorfields Eye Hospital, London, United Kingdom
  • Rose Richardson
    Development, Ageing and Disease, UCL Institute of Ophthalmology, London, United Kingdom
  • Andreas Mitsios
    Development, Ageing and Disease, UCL Institute of Ophthalmology, London, United Kingdom
  • Alessandro Abbouda
    Development, Ageing and Disease, UCL Institute of Ophthalmology, London, United Kingdom
  • Andrew Webster
    Development, Ageing and Disease, UCL Institute of Ophthalmology, London, United Kingdom
    Genetics, Moorfields Eye Hospital, London, United Kingdom
  • Footnotes
    Commercial Relationships   Mariya Moosajee, None; Rose Richardson, None; Andreas Mitsios, None; Alessandro Abbouda, None; Andrew Webster, None
  • Footnotes
    Support  Fight for Sight UK, Moorfields Eye Charity, NIHR, Choroideremia Research Foundation and Wellcome Trust
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4492. doi:
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      Mariya Moosajee, Rose Richardson, Andreas Mitsios, Alessandro Abbouda, Andrew Webster; Whole metabolomic profiling determines systemic dysfunction in Choroideremia. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4492.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations in the CHM gene, encoding the ubiquitous Rab Escort Protein 1 (REP1). REP1 is a component of the Rab geranyl-geranyl transferase II complex involved in prenylation of Rab proteins to facilitate their intracellular membrane trafficking. REP2, a compensatory isoform, fails to prenylate a subset of Rabs within the retina, leading to a tissue specific disease. Recently, significant plasma fatty acid and red blood cell membrane abnormalities were reported in CHM. In order to investigate this further, we undertook whole metabolome screening to investigate for any fatty acid dysregulation and whether CHM is a systemic disease.

Methods : Twenty-five affected male CHM patients and the equivalent age-matched healthy volunteers underwent whole metabolome profiling using the DiscoveryHD4™ platform (Metabolon), which uses multiple mass spectrometry methods to identify over 1,000 metabolites across all major classes, including amino acids, carbohydrates, lipids, nucleotides, energy, vitamins, and novel metabolites, from 100 μL of plasma extracted from a 5 ml blood sample. Exclusion criteria was taking medications for cholesterol or lipid modification.

Results : Over 800 known compounds were identified across the samples; 85 biochemicals were found to statistically differ (p<0.05, Welch’s Two Sample T-Test) between CHM patients and controls. Random Forest Confusion Matrix showed 86% predictive accuracy, indicating a high probability that individual metabolites are able to distinguish CHM from controls despite principal component analysis, showing similar global metabolic profiles. Overall, significant perturbation was found in (i) sphingolipid metabolism, (ii) broader lipid dysregulation, and (iii) the glutathione cycle which manages oxidative stress (increased in the CHM zebrafish retina).

Conclusions : Sphingolipids have a multicellular role, enriched in the plasma membrane, upon degradation in lysosomes, ceramide is hydrolysed to fatty acid and sphingosine. Rab proteins are associated with endocytosis and transport of sphingolipids. Spingolipid metabolism is disrupted in (i) diabetes causing endoplasmic reticulum stress and inflammation, and (ii) Alzheimer’s disease, with increased ceramide-mediated apoptosis. Further large-scale studies are required to ascertain the co-morbidity seen with CHM to establish a metabolic link.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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