Myocilin is a broadly expressed protein that when mutated uniquely causes glaucoma. While no function has been ascribed to explain focal disease, some properties of myocilin are known. Myocilin is a cytoplasmic protein that also localizes to vesicles specifically as part of a large membrane-associated complex with properties similar to the SNARE machinery that function in vesicle fusion. Its role in vesicle dynamics has not been detailed, however myocilin intersects with the endocytic compartment at the level of the multivesicular body. Since internalized GPCRs are sorted in the multivesicular body, we investigated whether myocilin functions in ligand-dependent GPR143 endocytosis. Using recombinant systems we found that the kinetics of myocilin recruitment to biotinylated membrane proteins was similar to that of arrestin-3. We also co-localized myocilin with GPR143 and Arrestin-2 by confocal microscopy. However, wild-type myocilin differed significantly in its association kinetics and co-localization with internalized proteins from mutant myocilin (P370L or T377M). Moreover, we found that myocilin bound to the cytoplasmic tail of GPR143, an interaction mediated by its amino terminal helix-turn-helix domain. Hydrodynamic analyses show that the myocilin-GPR143 protein complex is >158 kD and stable in 500 mM KCl, but not 0.1% SDS. Collectively, data indicate that myocilin is recruited to the membrane compartment, interacting with GPCR proteins during ligand-mediated endocytosis and that GPCR signaling underlies pathology in myocilin glaucoma.
BackgroundThe purpose of this study is to describe a patient who was diagnosed with granulomatosis with polyangiitis based on conjunctival biopsy. This study is a case report and review of the literature.FindingsA 48-year-old Caucasian woman presented with a 2-week history of a left eye peripheral corneal ulcer with adjacent conjunctivitis and a 4-month history of a non-resolving productive cough. Given her elevated serum perinuclear antineutrophil cytoplasmic antibody (P-ANCA) and erythrocyte sedimentation rate (ESR) levels as well as a chest computed topography (CT) that showed bilateral patchy infiltrates, suspicion of limited granulomatosis with polyangiitis with lung and ocular involvement was high. Because bronchoalveolar lavage was nondiagnostic for granulomatous disease, conjunctival biopsy was initially attempted in order to avoid a more invasive lung biopsy. The conjunctival biopsy revealed mixed subacute inflammatory mediators and vasculitis consistent with granulomatosis with polyangiitis.ConclusionsConjunctival biopsy may be a valuable, minimally invasive method for diagnosing systemic granulomatosis with polyangiitis.
Charles Bonnet syndrome (CBS) is a condition of visual hallucinations or disturbances occurring in patients with visual pathway pathology not due to underlying psychiatric, metabolic, or neurologic disease. A patient with Parkinson's disease experiencing visual hallucinations was evaluated by the ophthalmology service and found to have decreased vision due to bilateral reversible posterior capsular opacification. The patient's hallucinations did not improve on clozapine, a medication requiring careful monitoring due to potentially severe systemic side effects. However, the hallucinations resolved and vision improved after bilateral treatment of the posterior capsular opacification. Clozapine was then discontinued, and the patient was able to resume his previous Parkinson's disease therapy. This case highlights the importance of considering visual pathway pathology as a contributing factor to visual hallucinations, even in patients with previously diagnosed underlying psychiatric, metabolic, or neurologic disease that could additionally be the etiology of the visual disturbances.
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