OCRL1

OCRL1, or OCRL-1, is an inositol polyphosphate 5-phosphatase encoded by the OCRL gene on the X chromosome (Xq25–q26). It hydrolyzes the 5-phosphate of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 4-phosphate (PI(4)P), thereby regulating phosphoinositide signaling and membrane trafficking.

Localization and function: OCRL-1 localizes to the Golgi apparatus and endosomal membranes, where it participates in endocytic recycling and controls the levels of PIP2 at intracellular membranes. By shaping phosphoinositide composition, OCRL-1 influences vesicle formation, trafficking between endosomes and the Golgi, and receptor recycling.

Clinical significance: Pathogenic variants in OCRL cause Lowe syndrome (oculocerebrorenal syndrome), an X-linked disorder characterized by congenital cataracts, neurodevelopmental impairment, and proximal renal tubular dysfunction (Fanconi-type). In addition, OCRL mutations underlie Dent disease type 2, a proximal tubulopathy with low molecular weight proteinuria and phosphate wasting; phenotypes can overlap with Lowe syndrome, and female carriers may show milder features due to X-inactivation.

Genetics and pathophysiology: The OCRL gene is on the X chromosome. Mutations include missense, nonsense, splice-site, and larger rearrangements, resulting in loss or reduction of OCRL-1 activity. Deficiency disrupts endocytic trafficking and phosphoinositide balance, contributing to abnormal endosomal processing and proximal tubule dysfunction that underlies kidney, ocular, and neurologic manifestations.

Diagnosis and treatment: Diagnosis is based on clinical features supported by molecular genetic testing of OCRL. There is no cure; management is multidisciplinary and supportive, addressing renal Fanconi syndrome, cataracts, and neurodevelopmental needs.