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Abstract #25640 Published in IGR 12-2
Mutation of Lyst in mice recapitulates aspects of human exfoliation syndrome
Trantow CM; Anderson MGPigment Cell and Melanoma Research 2009; 22: 499
Exfoliation syndrome (XFS) is a common age-related disorder that can lead to glaucoma. One feature of XFS is a striking pattern of iris transillumination defects which we have discovered are recapitulated in mice containing the Lyst(bg-J) mutation. Lyst mutations were previously known to influence organelle biogenesis and cause partial albinism associated with Chediak-Higashi syndrome, but a link between Lyst and XFS was unsuspected. The goals of these experiments were to study mechanisms causing the Lyst-mediated iris defect and use this easily assayed trait to conduct genetic modifier screens. From histological analysis, we found that the iris defects of B6-Lyst(bg-J) mice involve degeneration of neural crest derived stromal melanocytes and adoption of an unusual 'saw-toothlike' morphology within the iris pigment epithelium. Molecularly, we found that the molecular basis of the bg-J mutation is a result of a three base pair deletion in the WD40 encoding region of the Lyst gene. Previously it has been shown that the LYST WD40 domain interacts with CSNK2B, an interaction we confirmed with GST-pulldown and demonstrated was completely disrupted by the LYST(bg-J) mutation. Thus, these results lead to a working hypothesis that one aspect of the Lyst- mediated iris phenotype likely involves CSNK2B, perhaps influencing cell-cell adherens junctions. As a means of gaining further mechanistic insight, we have also performed candidate- driven and phenotype-driven genetic modifier screens. From these experiments, we found that Tyr mutations rescue Lyst-mediated iris phenotypes while the DBA/2J genetic background enhances them. These findings suggest that pigment production is also an active factor.
C.M. Trantow. Molecular Physiology and Biophysics, University of Iowa, Iowa CityUnited States.
Classification:
9.4.4.1 Exfoliation syndrome (Part of: 9 Clinical forms of glaucomas > 9.4 Glaucomas associated with other ocular and systemic disorders > 9.4.4 Glaucomas associated with disorders of the lens)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
