LystMutation in Mice Recapitulates Iris Defects of Human Exfoliation Syndrome

Abstract

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. 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.

Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma

“…Anterior chamber phenotypes were assayed with a slit-lamp (SL-D7; Topcon) and photodocumented with a digital camera (D100; Nikon) as described previously (45). Gonioscopy was performed with a 2-mm gonioprism (Ocular Instruments).…”

Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome

“…This finally creates a premature stop codon that would truncate the protein after amino acid 2482 ( Figure 1B). Beige J mice carry an in-frame deletion of 3 nucleotides leading to deletion of isoleucine at position 3741 in the WD40 domain 23 BLOOD, 27 OCTOBER 2011 ⅐ VOLUME 118, NUMBER 17 For personal use only. on June 7, 2019. by guest www.bloodjournal.org From ( Figure 1B).…”

Lysosomal Trafficking Regulator (LYST)

“…Mutations of Lyst or disruption of LYST interacting proteins have also been suggested to be potential factors that contribute to exfoliation syndrome (XFS), a common age-related disease characterized by iris defects, fibrillar accumulations, and aberrantly dispersed pigment throughout the anterior chamber of the eye (Trantow et al 2009). A body of evidence suggests that the pathologic accumulation of exfoliative material within the iridocorneal angle elevates intraocular pressure (IOP) and leads to glaucoma (Trantow et al 2009;Trantow et al 2010).…”

“…A body of evidence suggests that the pathologic accumulation of exfoliative material within the iridocorneal angle elevates intraocular pressure (IOP) and leads to glaucoma (Trantow et al 2009;Trantow et al 2010). XFS is the most commonly identified cause of secondary open-angle glaucoma.…”