Silencing of the<i>CHM</i>Gene Alters Phagocytic and Secretory Pathways in the Retinal Pigment Epithelium

Gordiyenko, N.; Fariss, Robert N.; Zhi, C.; MacDonald, Ian M.

doi:10.1167/iovs.09-4117

Cited by 60 publications

(50 citation statements)

References 43 publications

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“…For quantitation of colocalization, Pearson's correlation coefficient was calculated with the JACoP plugin within ImageJ software (NIH). 28 At least 50 cells were analyzed for each experimental group.…”

Section: Indirect Immunofluorescence Staining and Confocal Microscopymentioning

confidence: 99%

Subcellular Distribution and Activity of Mechanistic Target of Rapamycin in Aged Retinal Pigment Epithelium

Zhao

et al. 2014

Investigative Ophthalmology & Visual Science

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Section: Indirect Immunofluorescence Staining and Confocal Microscopymentioning

confidence: 99%

Subcellular Distribution and Activity of Mechanistic Target of Rapamycin in Aged Retinal Pigment Epithelium

Zhao

et al. 2014

Investigative Ophthalmology & Visual Science

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“…The REP2-Rab27a complex was shown to have a lower affinity for GGTase-II compared with REP1-Rab27a. Defects in intracellular membrane traffic pathways, including melanosome transport and phagosome processing, were described for the defective REP-1 protein 21. REP-1 was also shown to be essential for geranylgeranylation of RAB27A in lymphoblasts isolated from choroideremia patients, meaning that defective REP-1 results in an accumulation of unprenylated RAB27A, specifically in the RPE 22.…”

Section: Genes Implicated In General Prenylation-associated Retinal Dmentioning

confidence: 99%

Prenylation defects in inherited retinal diseases

et al. 2014

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Many proteins depend on post-translational prenylation for a correct subcellular localisation and membrane anchoring. This involves the covalent attachment of farnesyl or geranylgeranyl residues to cysteines residing in consensus motifs at the C-terminal parts of proteins. Retinal photoreceptor cells are highly compartmentalised and membranous structures, and therefore it can be expected that the proper function of many retinal proteins depends on prenylation, which has been proven for several proteins that are absent or defective in different inherited retinal diseases (IRDs). These include proteins involved in the phototransduction cascade, such as GRK1, the phosphodiesterase 6 subunits and the transducin γ subunit, or proteins involved in transport processes, such as RAB28 and retinitis pigmentosa GTPase regulator (RPGR). In addition, there is another class of general prenylation defects due to mutations in proteins such as AIPL1, PDE6D and rab escort protein-1 (REP-1), which can act as chaperones for subsets of prenylated retinal proteins that are associated with IRDs. REP-1 also is a key accessory protein of geranylgeranyltransferase II, an enzyme involved in the geranylgeranylation of almost all members of a large family of Rab GTPases. Finally, mutations in the mevalonate kinase (MVK) gene, which were known to be principally associated with mevalonic aciduria, were recently associated with non-syndromic retinitis pigmentosa. We hypothesise that MVK deficiency results in a depletion of prenyl moieties that affects the prenylation of many proteins synthesised specifically in the retina, including Rabs. In this review, we discuss the entire spectrum of prenylation defects underlying progressive degeneration of photoreceptors, the retinal pigment epithelium and the choroid.

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“…In zebrafish rep1 mutants, photoreceptor degeneration has been suggested to be nonautonomous and only dependent on contact with mutant RPE [69]. In support of that finding, depletion of REP1 in human RPE cells does not affect the internalization of photoreceptor outer segments but rather reduces their degradation within the RPE [70]. These data suggest that the primary layer affected in CHM may be the RPE, if the data from mouse and zebrafish studies can be extrapolated to humans.…”

Section: Natural History and Selection Of Outcome Measuresmentioning

confidence: 86%

Pathogenic mechanisms and the prospect of gene therapy for choroideremia

Dimopoulos¹,

Chan²,

MacLaren

et al. 2015

Expert Opinion on Orphan Drugs

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Introduction Choroideremia is a rare, X-linked disorder recognized by its specific ocular phenotype as a progressive degenerative retinopathy resulting in blindness. New therapeutic approaches, primarily based on genetic mechanisms, have emerged that aim to prevent the progressive vision loss. Areas covered This article will review the research that has progressed incrementally over the past two decades from mapping to gene discovery, uncovering the presumed mechanisms triggering the retinopathy to preclinical testing of potential therapies. Expert opinion While still in an evaluative phase, the introduction of gene replacement as a potential therapy has been greeted with great enthusiasm by patients, advocacy groups and the medical community.

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Silencing of theCHMGene Alters Phagocytic and Secretory Pathways in the Retinal Pigment Epithelium

Cited by 60 publications

References 43 publications

Subcellular Distribution and Activity of Mechanistic Target of Rapamycin in Aged Retinal Pigment Epithelium

Subcellular Distribution and Activity of Mechanistic Target of Rapamycin in Aged Retinal Pigment Epithelium

Prenylation defects in inherited retinal diseases

Pathogenic mechanisms and the prospect of gene therapy for choroideremia

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