Neurodevelopmental origin of seizures in Lowe syndrome

Lowe syndrome (LS) is a rare X-linked monogenic disorder resulting from mutations in the OCRL1 gene that encodes a phosphatidylinositol 4,5-bisphosphate 5’ phosphatase enzyme. Patients with LS exhibit a range of neurological symptoms, including neurodevelopmental delays, hypotonia, febrile seizures, and behavioural abnormalities; however, the cellular and developmental origins of LS remain poorly understood. The Drosophila genome encodes a single homolog of OCRL ( docrl ). Here, we report that a germline null allele of docrl ( docrl ^KO ) shows heat induced seizures reminiscent of the febrile seizures in LS patients. Cell type specific deletion of docrl in neurons was sufficient to recapitulate the heat induced seizures seen in docrl ^KO indicating a cell autonomous requirement of docrl in neurons to prevent seizures. Temporally controlled deletion of docrl showed that heat induced seizure in adults were predetermined by a requirement of docrl in neural stem cells during embryonic neurogenesis. Collectively, our findings demonstrate the developmental origin of the neurological manifestations of LS highlighting the need to target potential therapeutic interventions during this developmental time window.