Role of ARMS2 mutations in age-related macular degeneration

PROJECT SUMMARY/ABSTRACT Genome-wide association (GWA) and linkage studies have identified >50 genes significantly associated with age related macular degeneration (AMD). However, many questions remain. Namely, are the identified GWA hits disease-causing variants or are they simply closely linked markers? And if the GWA hits are disease-causing variants, how do disruptions in these molecules lead to the observed pathologies? Further, since AMD is multifactorial, to what extent do particular combinations of factors precipitate AMD disease phenotypes or increase disease severity, as has been suggested to be the case in large scale GWA studies, where CFH and ARMS2/HTRA1 (locus on Chr. 10q26) appear to have synergistic effects on disease risk. Together they explain >50% of the genetic variability observed in AMD. Furthermore, since ARMS2 and HTRA1 are in strong linkage disequilibrium, it has been difficult to decipher whether either or both genes contribute to AMD-pathologies. The issues raised above can be addressed, in part, with appropriate animal models. Although mice do not have a macula per se, they faithfully recapitulate many aspects of retinal degenerative diseases and have been used to learn how disruption of certain molecules lead to AMD-like pathologies. In this application, we will seek in vivo confirmation of the cell-type and subcellular localization of ARMS2, and establish whether mice bearing the ARMS2A69S allele independently develop AMD-like sub-phenotypes and explore potential molecular mechanisms underlying the changes. Finally, because AMD is a multifactorial disease, we will examine if AMD- associated risk factors such as such as diet or genetic variants, such as CFH risk alleles, can potentiate AMD- like disease phenotypes. Identifying the pathogenic pathways and mechanisms underlying the disease sub-phenotypes, the goal of this proposal, is critical for developing effective therapies that can target the pre-symptomatic stage to prevent, delay onset or decrease severity of the disease. Animal models serve an important and unique role for furthering our understanding of the genetic underpinnings of disease, and as a resource to examine tissue pathology and to test therapeutics that cannot be readily done in humans.