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Martha Neuringer, Brett Jeffrey, Laurie Renner, Noelle Landauer, Ranjani Ramakrishnan, Jabob Luty, Peter J. Francis, Betsy Ferguson; Dominantly Inherited Early Onset Drusen in Japanese Macaques. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4008.
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Macaque monkeys possess a macula and provide a valuable model for studying age-related macular disease. Rhesus macaques commonly develop age-related maculopathy which shares common phenotypic features and genetic and nutritional risk factors with human age-related macular degeneration (AMD). We surveyed retinal status in a closely related species, the Japanese macaque (Macaca fuscata).
Color retinal fundus photography was used to document retinal phenotypes in 160 Japanese macaques from 1-32 years old. All were members of a troop resident at ONPRC since 1964. Selected cases underwent fluorescein angiography and electroretinography (ERG), including rod dark adaptation and full-field (ff) and restricted-field (rf; central 40°) measures of rod phototransduction. Central retinal function relative to full field was assessed by the rf:ff ratio for each ERG parameter. To begin exploration of candidate genes, we used RNAseq to identify potential heterozygous variants in an affected individual with both affected and unaffected offspring. RNA extracted from retinal and RPE tissue was sequenced on an Illumina GA IIx.
A pattern of early onset, dominantly inherited drusen was found in 42 colony members (26%). The phenotype was evident by 1-2 years of age, and size and number of drusen increased progressively with age. Drusen were found throughout the retina, with variable presence in the central macula. Affected animals showed no change in ERG rod sensitivity or dark adaptation, but had a reduced rf:ff ratio for Rmax, suggesting loss of central rod function. In genetic studies, 4 heterozygous variants were detected in ABCA4 exons 4, 11, 16 and 23, and 2 were detected in the 5'UTR of ELOVL4. However, analysis of additional individuals failed to demonstrate co-segregation of these variants with drusen status. No heterozygous variants were detected in EFEMP1 mRNA. Additional candidate genes are under review.
This retinal phenotype closely parallels human dominant drusen syndromes such as Malattia Leventinese/Doyne honeycomb dystrophy, which are phenotypically similar to AMD. A comparable syndrome was reported in cynomolgus macaques (Umeda et al., IOVS 46:683-691, 2005). This model complements the rhesus model of age-related maculopathy, and has the advantages that affected individuals can be identified at an early age and can be produced by selective breeding. Such animals can serve as a resource for preclinical testing of AMD therapies.
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