Abstract
Purpose :
To better understand exfoliative deposition, which is crucial for progression from exfoliation syndrome to exfoliation glaucoma.
Methods :
Using exome sequencing study to uncover XFS risk associated rare coding sequence variants that might have been missed by previous GWAS studies.
We established cell culture model with CYP39A1 loss of function alleles, measured metabolites, and performed deposition analysis.
Results :
Our recent exome sequencing study uncovered XFS risk associated rare coding sequence variants that might have been missed by previous GWAS studies. Several genes including LOXL1, were found to harbour a significant differential burden of rare, protein-altering genetic variants between patients with XFS and unaffected individuals; and the most significant targets were CYP39A1 loss of function alleles, which codes for an enzyme involved in the breakdown of cholesterol. Although LOXL1 is well known to be the major component of exfoliative deposits, and colocalizes with extracellular matrix (ECM) components, mutations in LOXL1 protect against XFS. We hypothesis that CYP39A1 loss of function increases XFG risk through LOXL1. Using risk alleles to predict XFS showed that incorporation of LOXL1 and CYP39A1 variants into XFS risk prediction algorithms improved the accuracy. Experiments on human RPE cells revealed that CYP39A1 loss of function alleles induced cholesterol depletion and accumulation of 24-hydroxycholesterol (24-OHC), resulting in the deposition of LOXL1 onto the ECM. The extent of deposition correlated with mutational status of LOXL1. Further mechanistic studies and mouse model experiments are ongoing.
Conclusions :
By focusing on LOXL1 and CYP39A1 alleles, we have identified a link between lipid metabolism/transport to proteostasis, increasing the understanding of exfoliative deposition that is crucial for progression from XFS to XFG.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.