Human Molecular Genetics Advance Access originally published online on November 23, 2007
Human Molecular Genetics 2008 17(5):710-716; doi:10.1093/hmg/ddm342
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Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people
1 Flinders Medical Centre, Department of Ophthalmology, Flinders University, Adelaide, Australia 2 Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia 3 Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Westmead, Australia and 4 Department of Ophthalmology, Royal Hobart Hospital, University of Tasmania, Hobart, Australia
* To whom correspondence should be addressed at: Department of Ophthalmology, Flinders University, Flinders Drive, Bedford Park, Adelaide 5042, South Australia. Tel: +61 8 8204 4624; Fax: +61 8 8277 0899; Email: jamie.craig{at}flinders.edu.au
Received October 23, 2007; Accepted November 21, 2007
Pseudoexfoliation syndrome is a generalized disorder of the extracellular matrix, characterized by the pathological accumulation of abnormal fibrillar material in the anterior segment of the eye predisposing to glaucomatous optic neuropathy. We investigated the role of lysyl oxidase-like 1(LOXL1) sequence variation in a Caucasian Australian population-based cohort of 2508 individuals, 86 (3.4%) of whom were diagnosed with pseudoexfoliation syndrome. Two non-synonymous variants in exon 1 of LOXL1 (Arg141Leu;Gly153Asp) were found to be strongly associated with pseudoexfoliation. Two copies of the high risk haplotype at these single-nucleotide polymorphisms conferred a risk of 7.20 (95%CI: 3.04–20.75) compared with no copies of the high risk haplotype. Each of the disease-associated alleles is by far commoner in the normal population, and examination of cross-species homology reveals that the two disease-associated coding variants belong to the ancestral version of the gene. LOXL1 was found to be expressed by reverse transcription–polymerase chain reaction in all ocular tissues examined except retina. The presence of LOXL1 protein in ocular tissues of interest was demonstrated by western blotting. Specific bands of 
130 and 80 kDa, representing polymerized protein forms, were detected in the cornea, iris, ciliary body, lens capsule and optic nerve. The 42 kDa mature form of LOXL1 was detected in the iris and ciliary body. Our Caucasian population has a 9-fold lower lifetime incidence of pseudoexfoliation syndrome compared with Nordic populations despite having similar allelic architecture at the LOXL1 locus. This strongly suggests that as yet unidentified genetic or environmental factors independent of LOXL1 strongly influence the phenotypic expression of the syndrome.
These authors contributed equally to this work.
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