CELL-LINES FROM KIDNEY PROXIMAL TUBULES OF A PATIENT WITH LOWE-SYNDROMELACK OCRL INOSITOL POLYPHOSPHATE 5-PHOSPHATASE AND ACCUMULATE PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE

The protein product of the gene that when mutated is responsible for L owe syndrome, or oculocerebrorenal syndrome (OCRL), is an inositol pol yphosphate 5-phosphatase. It has a marked preference for phosphatidyli nositol 4,5-bisphosphate although it hydrolyzes all four of the known inositol polyphosphate 5-phosphatase substrates: inositol 1,4,5-trisph osphate, inositol 1,3,4,5-tetrakisphosphate, phosphatidylinositol 4,5- bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate. The enzyme activity of this protein is determined by a region of 672 out of a to tal of 970 amino acids that is homologous to inositol polyphosphate 5- phosphatase II. Cell lines from kidney proximal tubules of a patient w ith Lowe syndrome and a normal individual were used to study the funct ion of OCRL. The cells from the Lowe syndrome patient lack OCRL protei n. OCRL is the major phosphatidylinositol 4,5-bisphosphate 5-phosphata se in these cells. As a result, these cells accumulate phosphatidylino sitol 4,5-bisphosphate even though at least four other inositol polyph osphate 5-phosphatase isozymes are present in these cells. OCRL is ass ociated with lysosomal membranes in control proximal tubule cell lines suggesting that OCRL may function in lysosomal membrane trafficking b y regulating the specific pool of phosphatidylinositol 4,5-bisphosphat e that is associated with lysosomes.