Lyst Mutation in Mice Recapitulates Iris Defects of Human Exfoliation Syndrome
Colleen Mary Trantow 1,
Mao Mao 1,
Greg Petersen 1,
Erin Alward 1,
Wallace L.M. Alward 2,
John Fingert 2,
and
Michael Anderson 3*
1 Molecular Physiology and Biophysics, The University of Iowa, Iowa City, Iowa, United States
2 Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States
3 Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, United States; Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States
* To whom correspondence should be addressed. E-mail: michael-g-anderson{at}uiowa.edu.
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Abstract |
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PURPOSE. Human eyes with exfoliation syndrome (XFS) exhibit a distinctive
pattern of iris transillumination defects that are recapitulated in Lyst mutant mice
carrying the beige allele. Here, we determine the anatomical basis for the Lyst-mediated transillumination defects, test whether Lyst mutant mice develop other features of XFS, and describe the molecular basis of the beige mutation.
METHODS. Lyst mutant mice and strain-matched controls were compared by
clinical, histological, immunohistochemical, and molecular genetic analyses.
RESULTS. Slit-lamp examination shows that Lyst mutant mice uniformly exhibit
XFS-like transillumination defects. Histological analysis shows that these defects
correlate with a "saw-tooth" morphology of the iris pigment epithelium. Lyst
mutant mice also produce an exfoliative-like material, and exhibit pronounced
pigment dispersion. Despite these insults, Lyst mutation does not cause increased intraocular pressure or optic nerve damage within the context of a C57BL/6J genetic background. Sequence analysis identifies that the beige mutation is predicted to delete a single isoleucine from the WD40 domain of the LYST protein, suggesting that this mutation is likely to disrupt a protein-protein interaction.
CONCLUSIONS. Lyst mutant eyes exhibit multiple features of XFS. Recent human genetic association studies have identified changes occurring in the LOXL1 gene as an important risk factor for development of XFS, but also indicated that other factors contributing to risk likely exist. Our results demonstrate that mutation of the Lyst gene can produce ocular features of human XFS and suggests that LYST or LYST-interacting genes may contribute to XFS.
Key Words:
glaucoma anterior segment, genetic diseases, iris, cell adhesion, exfoliation syndrome, mouse models
