CRISPR-Cas9 mouse model carrying the high-risk ARMS2 A69S AMD variant created to resolve chromosome 10q26 dispute

Researchers have posted a bioRxiv preprint describing the generation of a mouse model carrying the ARMS2 A69S variant, one of the highest-risk common genetic associations for age-related macular degeneration (AMD). AMD is the leading cause of irreversible central vision loss in older adults, and the strongest genetic risk signal maps to chromosome 10q26 — a region containing two genes, ARMS2 and HTRA1, in strong linkage disequilibrium. This co-localisation has made it difficult to determine whether one or both genes contribute to AMD risk.

Because ARMS2 orthologues are found only in higher primates and are absent from the rodent genome, no mouse model for ARMS2 biology has previously been available. The team used CRISPR-Cas9 to insert a humanised sequence carrying the A69S variant into the murine genome, creating the first mammalian model in which ARMS2 function can be interrogated in vivo. The preprint describes the characterisation of this model and its potential to resolve which gene or genes at 10q26 are causally responsible for AMD risk.

This is a preprint and has not yet been peer-reviewed. The findings are of interest to researchers studying AMD genetics, retinal disease, and the use of CRISPR-based humanisation strategies to model variants at loci absent from conventional model organisms.