During FY2000, we identified a celllar phenotype in human fibroblasts from Lowe syndrome patients.The oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by bilateral congenital cataracts, renal Fanconi syndrome and mental retardation. Lowe syndrome is due to a deficiency of the ocrl1 protein, a phosphatidylinositol 4,5- bisphosphate (PIP2) 5-phosphatase localized to the trans-Golgi network. At present, it is not known how a defective PIP2 5-phosphatase produces the lens, kidney and brain phenotype in Lowe syndrome. The substrate for this phosphatase, PIP2, is an important lipid modulator of cellular processes such cell signaling, protein trafficking and actin polymerization. PIP2 has been consistently demonstrated to be a positive effector of actin polymerization in vitro. We report here the novel finding that Lowe fibroblasts have a reduction in actin stress fibers and respond more rapidly to depolymerizing agents than control cells. These results appear to differ from in vitro data in which elevated PIP2 levels increase actin polymerization. In addition to the reduced actin stress fiber staining, we also show that Lowe cells have an increase in punctate F-actin staining in the center of the cell, that co-localizes with the actin severing and capping protein, gelsolin. This punctate F-actin/gelsolin staining, absent in normal fibroblasts, is concentrated in a central region of the cell and does not coincide with the localization of trans-Golgi network markers. Interestingly, the actin severing activity of gelsolin is regulated by both PIP2 and Ca2+ that would be expected to be altered in Lowe cells. The discovery of a cellular actin phenotype in Lowe syndrome appears relevant to the clinical phenotype since actin polymerization plays a key role in the formation, maintenance and proper function of tight junctions and adherens junctions.
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