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Akiko Suga, Mao Nakayama, Zai-Long Chi, Atsushi Mizota, Nobuhiro Shimozawa, kazutoshi yoshitake, Takeshi Iwata; Characterization and Genetic Analysis of Cynomolgus Monkeys with Hereditary Macular Drusen. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1853.
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© ARVO (1962-2015); The Authors (2016-present)
Macular drusen are thought as a hallmark of early phase of age-related macular degeneration, but the mechanisms of extracellular debris accumulation between retinal pigment epithelium (RPE) and Bruch′s membrane is not clearly understood. We have previously reported a cynomolgus monkey pedigree with early-onset drusen accumulation (Umeda et al., IOVS 2005, Umeda et al., J FASEB 2005). To characterize the pathology and causal genes for this inherited symptom, cellular and genetic analyses were performed.
A Cynomolgus monkey (Macaca fascicularis) pedigree with early-onset macular drusen was used for pathological and genetic studies. Primary monkey retinal pigment epithelial (RPE) cells were examined for phagocytotic activity, tight junction formation, and autophagic activities. Whole exome sequencing (WES) of 13 affected and 9 normal monkeys from the pedigree was performed. Additionally, whole genome sequencing (WGS) was performed on 4 affected and 3 normal monkeys. The sequencing reads were mapped to the Rhesus monkey genome sequence (rheMac2), and analyzed for the structural variations and studied by linkage analyses.
RPE cells from drusen-affected monkeys showed lower phagocytotic activity. Two linkage analysis methods (MERLIN, Superlink-Online SNP) showed 15kb region with relatively high LOD score of 2.5 and 2.9, respectively in the chromosome 1. In this region, variations in 13 genes were co-segregated with the affected monkeys. We further filtered to 3 candidate genes based on the information of predicted damaging effect and protein function.
RPE cells from drusen monkeys were consistent with lower phagocytotic activity. Our genetic analysis suggested that a 15kb region in the chromosome 1 was related to the early-onset drusen phenotype of a cynomolgus monkey pedigree. Functional analysis of the 3 candidate genes will be discussed.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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