Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus

Michael A. Hauser, Inas F. Aboobakar, Yutao Liu, Shiroh Miura, Benjamin T. Whigham, Pratap Challa, Joshua Wheeler, Andrew Williams, Cecelia Santiago-Turla, Xuejun Qin, Robyn M. Rautenbach, Ari Ziskind, Michële Ramsay, Steffen Uebe, Lingyun Song, Alexias Safi, Eranga N. Vithana, Takanori Mizoguchi, Satoko Nakano, Toshiaki KubotaKen Hayashi, Shin Ichi Manabe, Shigeyasu Kazama, Yosai Mori, Kazunori Miyata, Nagahisa Yoshimura, Andre Reis, Gregory E. Crawford, Francesca Pasutto, Trevor R. Carmichael, Susan E. Susan, Mineo Ozaki, Tin Aung, Chiea Chuen Khor, W. Daniel Stamer, Allison E. Ashley-Koch, R. Rand Allingham

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (~40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a welldefined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1.We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1.We showthat this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.

Original languageEnglish (US)
Pages (from-to)6552-6563
Number of pages12
JournalHuman Molecular Genetics
Issue number22
StatePublished - Nov 15 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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