Genomic and Proteomic Pathophysiology of Pseudoexfoliation Glaucoma

Abstract

PEX stems from a pathologic elastotic process involving the cross-linking gene lysyl oxidase-like-1 (LOXL1), and is associated with abnormal formation of elastic extracellular matrix. We previously described a protein sink model to explain PEX material deposition on the lens capsule and other intraocular surfaces. Recent research findings not only provide evidence to support this hypothesis, but also further our understanding of the fundamental disease process. A key aspect of the pathogenic process is the compromise of blood-aqueous barrier integrity in PEXG. Decreased level of LOXL1 is associated with decreased elastin incorporation into elastic tissues, including the elastic lamina of blood vessels. This results in unincorporated elastin that is released as soluble elastin, and leakage of serum proteins, inflammatory cytokines, and extracellular matrix components into aqueous humor. This ultimately leads to aggregation and precipitation of large protein complexes, or PEX material, throughout intraocular surfaces as described in the protein sink model. The pathologic PEX process also affects the biomechanical properties of elastic tissues, such as the trabecular meshwork, lens zonules, and lamina cribrosa. This may be part of the primary pathologic process with intrinsically altered extracellular matrix proteins. This fundamental change in the structural composition of these tissues may alter their rigidity, elasticity, and other biomechanical properties. This likely contributes to increased trabecular meshwork outflow resistance and high intraocular pressure, and mechanical injury to retinal ganglion cell axons at the lamina cribrosa, which are conducive to glaucoma. These pathophysiologic processes combined may underlie some of the clinical hallmarks observed in PEXG.

Clinical spectrum of pseudoexfoliation syndrome—An electronic records audit

“…The prevalence of PXF varies widely across the globe ranging from 0% in Eskimos, 1–2% in the United States, 5% in Turkish population to >25% in Scandinavian countries and Navajo Indians and between males and females. [ 1 , 5 , 6 , 13 , 14 , 27 – 29 ] Some postulated reasons included differences in environment, diet and lifestyle, differences in hours of outdoor exposure and distance from equator apart from basic difference in genetic susceptibility study design and lack of using slit lamp under dilated examination in many studies. In the Reykjavik Eye Study, prevalence increased from 2.5% in those aged 50–59 years to 40.6% in those aged≥ 80 years.…”

Association analysis of polymorphisms rs12997 in ACVR1 and rs1043784 in BMP6 genes involved in bone morphogenic protein signaling pathway in primary angle-closure and pseudoexfoliation glaucoma patients of Saudi origin

“…Likewise, PXG is a severe form of open-angle glaucoma associated with worse prognosis. PXG is characterized by the abnormal deposition of pseudoexfoliative material (fibrillar extracellular matrix (ECM)) in the anterior segment of the eye causing the obstruction [35]. It is difficult to elucidate the precise mechanism(s) by which the variant rs12997 in ACVR1 may influence the risk of these glaucoma types.…”

Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors

“…Guo et al recently identified the LOX mutation that causes familial TAAD: the Ser280Arg mutation produced a less active variant that led to disorganised elastic fibres and increased collagen in patients’ aortas [127]. Several reports have described an association between LOXL1 and glaucoma, specifically in the early stages of the elastic fibre disorder exfoliation syndrome (XFS) [76,[128], [129], [130], [131]]. LOXL1 colocalised with elastin, fibrillin-1 and fibulin-4, which were also upregulated, and its expression was enhanced by TGFβ1 and other XFS-associated stimuli in Tenon’s capsule fibroblasts [76].…”