Sakar, Hajrah;
Tracey-White, Dhani;
Hagag, Ahmed M;
Burgoyne, Thomas;
Nair, Neelima;
Jensen, Lasse D;
Edwards, Malia M;
(2024)
Loss of REP1 impacts choroidal melanogenesis and vasculogenesis in choroideremia.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
, 1870
(2)
, Article 166963. 10.1016/j.bbadis.2023.166963.
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Abstract
Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy affecting the photoreceptors, retinal pigment epithelium (RPE) and choroid, however, the involvement of the choroid in disease progression is not fully understood. CHM is caused by mutations in the CHM gene, encoding the ubiquitously expressed Rab escort protein 1 (REP1). REP1 plays an important role in intracellular trafficking of vesicles, including melanosomes. In this study, we examined the ultrastructure of the choroid in chmru848 fish and Chmnull/WT mouse models using transmission electron and confocal microscopy. Significant pigmentary disruptions were observed, with lack of melanosomes in the choroid of chmru848 fish from 4 days post fertilisation (4dpf), and a reduction in choroidal blood vessel diameter and interstitial pillars suggesting a defect in vasculogenesis. Total melanin and expression of melanogenesis genes tyr, tryp1a, mitf, dct and pmel were also reduced from 4dpf. In Chmnull/WT mice, choroidal melanosomes were significantly smaller at 1 month, with reduced eumelanin at 1 year. The choroid in CHM patients were also examined using spectral domain optical coherence tomography (SD-OCT) and OCT-angiography (OCT-A) and the area of preserved choriocapillaris (CC) was found to be smaller than that of overlying photoreceptors, suggesting that the choroid is degenerating at a faster rate. Histopathology of an enucleated eye from a 74-year-old CHM male patient revealed isolated areas of RPE but no associated underlying CC. Pigmentary disruptions in CHM animal models reveal an important role for REP1 in melanogenesis, and drugs that improve melanin production represent a potential novel therapeutic avenue.
| Type: | Article |
|---|---|
| Title: | Loss of REP1 impacts choroidal melanogenesis and vasculogenesis in choroideremia |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bbadis.2023.166963 |
| Publisher version: | https://doi.org/10.1016/j.bbadis.2023.166963 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Choroideremia, Transmission electron microscopy, Melanogenesis, Vasculogenesis, Optical coherence tomography |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10181937 |
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