Exfoliation syndrome (XFS) is a common age-related disorder primarily recognized by the pathologic accumulations of a fibrillar exfoliative material in the anterior chamber of the eye but also associated with several other ocular and systemic abnormalities.1–6
In many patients, accumulation of exfoliative material within the iridocorneal angle is accompanied by elevated intraocular pressure (IOP) and glaucoma. Indeed, XFS is the most commonly identified cause of secondary open-angle glaucoma.7
In parallel to the clinical significance of exfoliative material in the diagnosis of XFS, much of the experimental work on XFS syndrome has focused on studies of exfoliative material. Such studies have shown that exfoliative material consists of an irregular conglomeration of randomly cross-banded fibrils approximately 30 nm in diameter surrounded by an amorphous matrix of glycoconjugates.8
Exfoliative material also contains epitopes for a variety of proteins related to elastic microfibers, including fibrillin-1,9
These results and other experimental work on XFS have led to a hypothesis that XFS is a disease of elastosis. According to this theory, insults such as increased oxidative stress and elevated levels of TGF-β
1 likely trigger increased production of elastic microfibrils that are subsequently prone to aggregate and accumulate.4
After aggregation and accumulation of exfoliative material within the anterior chamber, aqueous humor outflow becomes impeded, ultimately resulting in increased IOP and glaucoma.
A breakthrough in understanding XFS has been precipitated by genomewide association studies that have begun to unravel the genetic factors underlying XFS. XFS has long been appreciated to have strong hereditary contributions.12,13
Recently, the lysyl oxidase-like protein 1 gene (LOXL1
) has been identified as the first known genetic risk factor contributing to XFS.14
Initially identified from a large genomewide association study among Scandinavian patients with glaucoma14
and subsequently replicated in additional populations,15–24
a strong association exists between XFS and two single nucleotide polymorphism (SNP) genetic markers resulting in nonsynonymous changes (rs1048661, R141L; rs3825942, G153D) in LOXL1
. These LOXL1
SNPs are highly associated with XFS, and the high-risk alleles of these SNPs occur within most XFS patients. The high-risk haplotype of LOXL1
alleles has a 99% population attributable risk in Caucasian populations.14
However, the influence of LOXL1
in XFS may not be as straightforward as is seemingly indicated by these impressive statistics.
A multifactorial risk for XFS is suggested by the extremely high occurrence of high-risk LOXL1
alleles among the general population. Within the original Scandinavian populations studied, the high-risk haplotype of LOXL1
alleles was also detected at a frequency of approximately 50% in the general population, with approximately 25% of the general population homozygous for the haplotype.14
Follow-up studies have also confirmed similar high-carrier frequencies.15–24
Thus, most people with high-risk LOXL1
alleles likely do not have XFS. This indicates that although LOXL1
is an important risk factor for XFS, additional factors must play a role in the pathogenesis of the condition.
Here, we identify the Lyst gene as an additional gene potentially important to XFS. B6-Lystbg-J mice homozygous for the beige-J (bg-J) allele recapitulate multiple ocular features of human XFS. Our initial consideration of B6-Lystbg-J mice as a possible model of XFS was based on a resemblance of iris transillumination defects between these mice and human patients with XFS. In testing the anatomic basis for the Lyst-mediated transillumination defects, we found that the transillumination defects were caused by an unusual sawtooth-like morphology of the iris pigment epithelium and were accompanied by the presence of a material resembling human exfoliative material. Interestingly, the molecular basis of the beige mutation was discovered to be a 3-bp deletion. The mutation is predicted to delete a single isoleucine from the carboxyl terminus of the LYST protein within the WD40 domain, potentially disrupting a protein-protein interaction. This work represents one of the first descriptions of a mouse model potentially relevant to XFS and provides a genetic resource for continued study of this novel molecular pathway contributing to XFS.