Lowe syndrome is an X‐linked recessive disorder caused by mutations in OCRL, which encodes the phosphatidylinositol 5′‐phosphatase OCRL1. Hallmark symptoms of Lowe syndrome include proximal tubule (PT) dysfunction, typically characterized by low molecular weight proteinuria (LMWP), renal tubular acidosis, aminoaciduria, and hypercalciuria. OCRL1 has been hypothesized to play a role in myriad cellular processes including membrane trafficking, actin dynamics, cell polarity, ciliogenesis, and cell division. However, consensus is lacking for how loss of OCRL1 leads to impaired PT function. To this end, we created a PT cell culture model of the disease. Using the CRISPR/Cas9 genome editing system, we knocked out OCRL1 expression in a human PT cell line. In parallel, we transiently knocked down OCRL1 using siRNA to confirm that chronic depletion did not result in cell adaptation. Neither acute nor chronic depletion of OCRL1 had any effect on endocytic uptake of the megalin/cubilin ligand albumin. However, OCRL1 depleted cells consistently proliferated more slowly and exhibited a higher percentage of multinucleated cells than matched controls. We hypothesize that defects in cell division during kidney development and/or repair after kidney injury may compromise PT length and/or diameter in patients and have developed a mathematical model to assess the effect of such changes on PT albumin uptake. Our data suggest a new explanation for how loss of OCRL1 function results in LMWP as well as the other commonly observed renal manifestations of Lowe syndrome.Support or Funding InformationNational Institutes of Health R01‐DK101484, R01‐DK100357, P30‐DK079307, T32‐DK061296; Lowe Syndrome Association