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M. Neuringer, N. Landauer, P. Wallace, B.M. Ferguson; Complement Factor H Polymorphisms and Drusen in Rhesus Monkeys . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4341.
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To characterize Complement Factor H (CFH) gene polymorphisms in rhesus monkeys and determine their relationship to early–onset and age–related macular drusen.
Retinal fundus stereophotographs were obtained from over 600 rhesus macaques (Macaca mulatta). Photographs were graded for the presence and severity of macular drusen. To explore whether CFH polymorphisms were associated with drusen, we sequenced the CFH exon 9 region and identified single nucleotide polymorphisms (SNPs) in both affected (age 8–25) and unaffected (age 18–25) monkeys. These included unrelated animals as well as members of a large family (61 members) with high drusen prevalence. We translated the exon 9 DNA sequence of typical unaffected and affected individuals, and compared the predicted proteins to each other and to the human CFH sequence.
The prevalence of drusen rose to 40–45% by 13–16 years of age. Moderate–to–severe cases rose to 18–20% by 17–20 years of age and to 35% by age 25 (equivalent to 75 human years); they were found predominately in females, and were 2–4 times more common in rhesus monkeys of Chinese origin compared with those of Indian origin at ages 9–16. No monkeys were identified with geographic atrophy or neovascular disease. Twelve families were found with a high prevalence (>50%) and/or early onset of drusen. In CHF exon 9, 26 SNPs were detected, with the alleles distributed into two distinct genotypic patterns that were differentially associated with affected and unaffected status both within and across families. Six amino acids differed consistently between the human and rhesus protein, and an additional six amino acids in the affected animal sequence differed from residues found conserved in the unaffected monkey and human protein sequences. These latter substitutions included Tyr398His, Pro423Arg, Lys424Asn, Thr430Asn, Thr439Pro and Arg444His.
Exon 9 of the rhesus monkey CFH gene is a region rich in SNPs, and some of these may be associated with development of drusenoid maculopathy. Given the proximity of the detected amino acid substitutions to the Tyr402His change associated with human age–related macular degeneration, we speculate that one or more of these changes may contribute to drusen formation in rhesus macaques. Sequencing of a large number of additional monkeys will be necessary to confirm the generality of the results. Confirmation of similar genetic susceptibility factors in human and nonhuman primates would provide the basis for studies of disease mechanisms and gene–environment interactions in an optimal animal model.
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