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Editors Selection IGR 9-3

Genetics: Gene encoding in XFG

Comment by Rosario Hernandez on:

19653 Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma, Thorleifsson G; Magnusson KP; Sulem P et al., Science, 2007; 317: 1397-1400

See also comment(s) by Rand Allingham • Wallace Alward •

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Thorleifsson et al. (890) describe three single nucleotide polymorphisms (SNPs) in the gene encoding for lysyl oxidase like 1(LOXL1) with strong genetic association with exfoliation glaucoma (XFG) and that confer high risk for XFG in patients with exfoliation syndrome (XFS). The paper demonstrated that LOXL1 gene variations associate with XFG but not with POAG. The LOXL1 gene is located on chromosome 15q24.1 and the SNPs are in the first intron and exon 1. LOXL1 is important in assembly of elastic fibers through polymerization of tropoelastin monomers. Pathological assembly and production of elastin microfibrils causes accumulation of pseudoexfoliation material (PEX) in XFG in the anterior segment of the eye and, in many patients, obstruct the outflow pathway causing elevated IOP. LOXL1 also associates with Fibulin 5 (FIB5) causing tropoelastin polymerization into fibers. Fib5 is part of PEX material. PEX is found in many organs that contain elastic fibers; however, no systemic diseases are known. The authors also investigated the expressions of the LOXL1 variants using microarray analyses of adipose tissue in a subset of individuals. A small decrease in LOXL1 gene expression in individuals that carry two copies of the risk G allele in rs1048661 was found and there was a weaker association for the other variants. The variant rs3825942s which confers the highest risk for XFG does not affect gene expression. Deletion of LOXL1 in mice produces cardiovascular and uterine abnormalities but no ocular phenotype (Liu et al., Nat. Gen. 2005).

Alterations in ECM assembly and maintenance may provide susceptibility of the optic nerve head to elevated intraocular pressure

Thus, the molecular mechanisms by which SNPs cause XFG are unknown. In the optic nerve head (ONH), elastotic degeneration occurs in POAG and elastosis is prominent in XFG. The new data on LOXL1 suggest that elastic fiber maintenance in the ONH is abnormal in XFG. Recently, we reported that African American ONH astrocytes exhibit decreased elastic fiber maturation and a concomitant decrease of LOXL2 expression (Urban et al., IOVS 2007). We have suggested structural ECM differences in the ONH of this population. The findings of Thorleifsson et al. strongly support the concept that alterations in ECM assembly and maintenance may provide susceptibility of the ONH to elevated IOP, causing glaucomatous optic neuropathy and/or underlying the progression of glaucomatous damage.

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