Establishment and validation of an in-vitro model for Lowe syndrome and Dent II Disease

Lowe Syndrome and Dent II disease are two rare X-linked genetic disorders affecting children with phenotypes seen in eye, brain, and kidney. Mutations in the OCRL gene, which encodes the inositol polyphosphate 5-phosphatase (OCRL1), are responsible for causing dysfunction in the proximal tubule cells of kidney, congenital cataracts in eye, muscle hypotonia, and intellectual disabilities in children. OCRL1 prefers PtdIns(4,5)P2 and PtdIns(3,4,5)P3 as its substrate and maintains phosphoinositide homeostasis along the endolysosomal pathway. The homeostasis, when disrupted, causes inhibition of many important cellular processes, such as defective ciliogenesis, impaired receptor recycling, transport defect from endosomes to trans-Golgi network, and proper functioning of lysosomes. The mechanistic understanding of Lowe Syndrome and Dent II disease still evades us, perhaps due to limitations and absence of better in-vitro disease models, which can physiologically mimic the diseased state.