Properties and Therapeutic Implications of an Enigmatic D477G RPE65 Variant Associated with Autosomal Dominant Retinitis Pigmentosa
| Autor: | Robert K. Koenekoop, Peter Humphries, Anna-Sophia Kiang, Marian M. Humphries, G. Jane Farrar, Matthew Campbell, Ema Ozaki, Paul F. Kenna |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
knock-in mouse models 0301 basic medicine Leber Congenital Amaurosis Review RPE65 Disease medicine.disease_cause Choroideremia Mice chemistry.chemical_compound 0302 clinical medicine Protein Isoforms Gene Knock-In Techniques Age of Onset Genetics (clinical) Genes Dominant Genetics Mutation Clinical Trials Phase I as Topic incomplete penetrance Penetrance Pedigree Retinaldehyde Female autosomal dominant retinitis pigmentosa Retinitis Pigmentosa Retinal Dystrophies cis-trans-Isomerases DNA Complementary lcsh:QH426-470 Genetic Vectors 9-cis retinaldehyde Mutation Missense Biology Proof of Concept Study 03 medical and health sciences medicine Animals Humans Point Mutation Enzyme Replacement Therapy Gene Retinal Genetic Therapy medicine.disease eye diseases lcsh:Genetics 030104 developmental biology Amino Acid Substitution chemistry 030221 ophthalmology & optometry sense organs |
| Zdroj: | Genes Genes, Vol 11, Iss 1420, p 1420 (2020) |
| ISSN: | 2073-4425 |
| DOI: | 10.3390/genes11121420 |
| Popis: | RPE65 isomerase, expressed in the retinal pigmented epithelium (RPE), is an enzymatic component of the retinoid cycle, converting all-trans retinyl ester into 11-cis retinol, and it is essential for vision, because it replenishes the photon capturing 11-cis retinal. To date, almost 200 loss-of-function mutations have been identified within the RPE65 gene causing inherited retinal dystrophies, most notably Leber congenital amaurosis (LCA) and autosomal recessive retinitis pigmentosa (arRP), which are both severe and early onset disease entities. We previously reported a mutation, D477G, co-segregating with the disease in a late-onset form of autosomal dominant RP (adRP) with choroidal involvement; uniquely, it is the only RPE65 variant to be described with a dominant component. Families or individuals with this variant have been encountered in five countries, and a number of subsequent studies have been reported in which the molecular biological and physiological properties of the variant have been studied in further detail, including observations of possible novel functions in addition to reduced RPE65 enzymatic activity. With regard to the latter, a human phase 1b proof-of-concept study has recently been reported in which aspects of remaining vision were improved for up to one year in four of five patients with advanced disease receiving a single one-week oral dose of 9-cis retinaldehyde, which is the first report showing efficacy and safety of an oral therapy for a dominant form of RP. Here, we review data accrued from published studies investigating molecular mechanisms of this unique variant and include hitherto unpublished material on the clinical spectrum of disease encountered in patients with the D477G variant, which, in many cases bears striking similarities to choroideremia. |
| Databáze: | OpenAIRE |
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