K.A. Howes

Elovl4 haploinsufficiency does not induce early onset retinal degeneration in mice

ELOVL4 was first identified as a disease-causing gene in Stargardt macular dystrophy (STGD3, MIM 600110.) To date, three ELOVL4 mutations have been identified, all of which result in truncated proteins which induce autosomal dominant juvenile macular degenerations. Based on sequence homology, ELOVL4 is thought to be another member within a family of proteins functioning in the elongation of long chain fatty acids. However, the normal function of ELOVL4 is unclear. We generated Elovl4 knockout mice to determine if Elovl4 loss affects retinal development or function. Here we show that Elovl4 knockout mice, while perinatal lethal, exhibit normal retinal development prior to death at day of birth. Further, postnatal retinal development in Elovl4 heterozygous mice appears normal. Therefore haploinsufficiency for wildtype ELOVL4 in autosomal dominant macular degeneration likely does not contribute to juvenile macular degeneration in STGD3 patients. We found, however, that Elovl4+/- mice exhibit enhanced ERG scotopic and photopic a and b waves relative to wildtype Elovl4+/+ mice suggesting that reduced Elovl4 levels may impact retinal electrophysiological responses.

10q26 Is Associated with Increased Risk of Age-Related Macular Degeneration in the Utah Population

Age-related macular degeneration (AMD) includes a wide range of phenotypes. Early AMD is mainly characterized by the presence of soft dusen in the macula without visual loss, while advanced AMD is characterized by geographic atrophy (GA or dry AMD) and neovascular AMD (wet AMD) with visual loss. Despite the rising prevalence of AMD as a result of increasing life expectancy, its underlying etiology is poorly understood and there is no specific therapy. Nutritional supplements and antagonists of vascular endothelial growth factor (VEGF) have been reported to halt the progression of visual loss in wet AMD (Bressler et al., 1988). Wet AMD is usually associated with an aggressive form of visual loss due to choroidal neovascularization (CNV). Previous reports by several groups have identified a significant association between a common missense variant (Y402H) and non-coding variants in CFH and AMD in the United States (Edwards et al., 2005; Fisher et al., 2005; Hageman et al., 2005; Haines et al., 2005; Klein et al., 2005; Li et al., 2006; Maller et al., 2006) and Europe (Fisher et al., 2005; Souied et al., 2005; Despriet et al., 2006; Magnusson et al., 2006; Postel et al., 2006; Sepp et al., 2006; Simonelli et al., 2006). Recently, it was reported that rs10490924 in LOC387715 is the second major locus for AMD located at 10q locus (Conley et al., 2005; Rivera et al., 2005; Haddad et al., 2006; Maller et al., 2006; Schmidt et al., 2006). In this study we performed an association study incorporating SNP data for LOC387715 and PLEKHA1 at 10q26 and for CFH at 1q31.3 in the Utah AMD cohort. Our results support previous findings that

Progressive pathways in age-related macular degeneration

Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by progressive damage to supportive layers and photoreceptor cell loss. No current therapy halts vision loss. Numerous genetic and/or environmental factors likely contribute to the initiating events leading to AMD. Progressive events from cellular dysfunction and tissue destruction result in the histopathological features of AMD including drusen formation, basal laminar deposits, accumulation of lipofuscin in the retinal pigmented epithelium (RPE), thickening of Bruchs membrane, choriovasculature and RPE cell loss, and photoreceptor cell death. Studies on the biochemical and physiological perturbations seen in the RPE, Bruchs membrane and the choroid correlate well with AMD, however, progressive events leading to these characteristic features are not well understood. Resolving these issues is essential for successful therapeutic intervention of AMD. We propose that receptor-mediated cellular activation by advanced glycation end (AGE) products, a major contributor to progressive tissue damage in other aging disorders, may also contribute significantly to progressive damage in AMD. In this paper, we review and compare pathological features of AMD to AGE/RAGE- mediated progressive events incurred in other aging disorders.