Lyst mutation in mice recapitulates iris defects of human exfoliation syndrome.
OBJECTIVE
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. The purpose of this study was to determine the anatomic basis for 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, histologic, immunohistochemical, and molecular genetic analyses.


RESULTS
Slit-lamp examination showed that Lyst mutant mice uniformly exhibit XFS-like transillumination defects. Histologic analysis showed that these defects correlate with a sawtooth 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 in the C57BL/6J genetic background. Sequence analysis identified 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 XFS but also indicated that other factors contributing to risk likely exist. These results demonstrated that mutation of the Lyst gene can produce ocular features of human XFS and suggested that LYST or LYST-interacting genes may contribute to XFS.
Trantow
Colleen M
CM
Department of Molecular Physiology, University of Iowa, Iowa City, Iowa 52242, USA.
Mao
Mao
M
Petersen
Greg E
GE
Alward
Erin M
EM
Alward
Wallace L M
WL
Fingert
John H
JH
Anderson
Michael G
MG
D000818:Animals; D004195:Disease Models, Animal; D017889:Exfoliation Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007499:Iris Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010857:Pigment Epithelium of Eye / Q000473:pathology*; D011506:Proteins / Q000235:genetics*; D033921:Vesicular Transport Proteins
D047908:Intracellular Signaling Peptides and Proteins; C491133:Lyst protein, mouse; D011506:Proteins; D033921:Vesicular Transport Proteins