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Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people


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Hewitt, AW, Sharma, S, Burdon, KP, Wang, JJ, Baird, PN, Dimasi, DP, Mackey, DA, Mitchell, P and Craig, JE 2007 , 'Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people' , Human Molecular Genetics, vol. 17, no. 5 , pp. 710-716 , doi: 10.1093/hmg/ddm342.

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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 singlenucleotide
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.

Item Type: Article
Authors/Creators:Hewitt, AW and Sharma, S and Burdon, KP and Wang, JJ and Baird, PN and Dimasi, DP and Mackey, DA and Mitchell, P and Craig, JE
Journal or Publication Title: Human Molecular Genetics
ISSN: 0964-6906
DOI / ID Number: 10.1093/hmg/ddm342
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