June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
LOX gene polymorphisms are associated with keratoconus and predicted to affect protein structure
Author Affiliations & Notes
  • Yelena Bykhovskaya
    Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
    Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
  • Ayesha Rasheed
    Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
  • Yaron S Rabinowitz
    Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA
    Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
  • Footnotes
    Commercial Relationships Yelena Bykhovskaya, None; Ayesha Rasheed, None; Yaron Rabinowitz, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2042. doi:
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    • Get Citation

      Yelena Bykhovskaya, Ayesha Rasheed, Yaron S Rabinowitz; LOX gene polymorphisms are associated with keratoconus and predicted to affect protein structure. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2042.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Keratoconus (KC) is a bilateral non-inflammatory progressive corneal disorder with complex genetic inheritance. Polymorphisms in the Lysyl Oxidase gene (LOX) which encodes an enzyme responsible for collagen cross-linking in the corneal stroma have been repeatedly associated with genetic susceptibility to KC. We studied frequency of LOX variants in KC cases and control samples and modeled functional effects of these variants on the structure of LOX protein.

Methods: Genomic region surrounding the location of the previously identified LOX SNP rs18000449 associated with KC has been sequenced using Sanger sequencing in 97 Caucasian KC cases and 104 Caucasian control subjects. Protein structure modeling was performed using the RaptorX, I-TASSER, and Phyre2 web servers.

Results: In addition to the already known G473A polymorphism (dbSNP rs18000449, 5:122,077,513; global MAF 0.16) which results in the Arg158Gln amino acid substitution in the LOX propeptide we identified an adjacent variant C476A (dbSNP rs41407546, 5:122,077,510, global MAF 0.0018) which results in the Pro159Gln substitution of the amino acid residue located adjacent to the one affected by rs18000449. We found that 6 KC patients were carriers of the minor allele A of SNP rs41407546 (KC MAF=0.03) thus showing more than 10 times increased frequency compared to normal individuals. No controls were found to carry this rare variant. Interestingly, frequency of allele A of rs41407546 was even greater in carriers of minor allele A of rs18000449 (KC MAF=0.07). Protein structure models constructed for the wild-type and double mutant LOX proteins by several in-silico tools showed dramatic differences between projected protein structures.

Conclusions: Our results provide evidence that combination of common and rare LOX variants may lead to destabilization of the LOX protein potentially causing defects in collagenous corneal stroma associated with keratoconus.

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