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Browsing by Author "Alvarado, Jorge A."
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Item Defective INPP5E distribution in NPHP1‐related Senior–Loken syndrome(Wiley, 2021-01) Ning, Ke; Song, Emilie; Sendayen, Brent E.; Prosseda, Philipp P.; Chang, Kun-Che; Ghaffarieh, Alireza; Alvarado, Jorge A.; Wang, Biao; Haider, Kathryn M.; Berbari, Nicolas F.; Hu, Yang; Sun, Yang; Ophthalmology, School of MedicineBackground: Senior-Loken syndrome is a rare genetic disorder that presents with nephronophthisis and retinal degeneration, leading to end-stage renal disease and progressive blindness. The most frequent cause of juvenile nephronophthisis is a mutation in the nephronophthisis type 1 (NPHP1) gene. NPHP1 encodes the protein nephrocystin-1, which functions at the transition zone (TZ) of primary cilia. Methods: We report a 9-year-old Senior-Loken syndrome boy with NPHP1 deletion, who presents with bilateral vision decrease and cystic renal disease. Renal function deteriorated to require bilateral nephrectomy and renal transplant. We performed immunohistochemistry, H&E staining, and electron microscopy on the renal sample to determine the subcellular distribution of ciliary proteins in the absence of NPHP1. Results: Immunohistochemistry and electron microscopy of the resected kidney showed disorganized cystic structures with loss of cilia in renal tubules. Phosphoinositides have been recently recognized as critical components of the ciliary membrane and immunostaining of kidney sections for phosphoinositide 5-phosphatase, INPP5E, showed loss of staining compared to healthy control. Ophthalmic examination showed decreased electroretinogram consistent with early retinal degeneration. Conclusion: The decreased expression of INPP5E specifically in the primary cilium, coupled with disorganized cilia morphology, suggests a novel role of NPHP1 that it is involved in regulating ciliary phosphoinositide composition in the ciliary membrane of renal tubular cells.Item Intraluminal Deposits Found in Glaucoma Tube Shunts Via Anterior Segment Ocular Coherence Tomography(Lippincott, Williams & Wilkins, 2018-03) Alvarado, Jorge A.; Srivastava, Vinita; Sun, Yang; Medicine, School of MedicinePURPOSE: To describe and characterize a novel observation of intraluminal deposits of glaucoma tube shunts (TS) using spectral domain (SD) ocular coherence topography (OCT). PATIENTS AND METHODS: Fifteen TS in 11 patients diagnosed with primary open-angle, neovascular, aphakic, and uveitic glaucomas. Both Ahmed (n=11) and Baerveldt (n=4) TS were examined with 5-line raster anterior segment SD-OCT imaging. RESULTS: The exposed tubes of 2 patients had highly reflective intraluminal deposits in the corresponding exposed areas. Seven tubes without exposure had a thin rim of highly reflective material. Six tubes were clear of luminal deposits. The most common diagnosis in the study was uveitic glaucoma which occurred in 5 of the 15 eyes (33%). The next most common diagnosis was primary open-angle glaucoma which occurred in 4 of the 15 eyes (25%). There were 2 nonvalved Baerveldt tubes in each group. The mean duration of TS implantation was 15.0 months in the deposit group and 33.7 months in the group without luminal deposits. The majority of patients in each group were using eye drops at presentation (88.9% deposit, 83.3% clear), and the average intraocular pressure was 20.2 mm Hg in the deposit group and 19.0 mm Hg in the clear group. CONCLUSIONS: Anterior segment OCT imaging may be used to evaluate TS integrity. Intraluminal deposits in TS may occur as a natural response to implanted drainage device, possibly as an inflammatory response.Item Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome(The Company of Biologists, 2017-10-15) Prosseda, Philipp P.; Luo, Na; Wang, Biao; Alvarado, Jorge A.; Hu, Yang; Sun, Yang; Ophthalmology, School of MedicineLowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl-null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P2 in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.