LOWE-SYNDROME, A DEFICIENCY OF A PHOSPHATIDYL-INOSITOL 4,5-BISPHOSPHATE 5-PHOSPHATASE IN THE GOLGI-APPARATUS

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, renal tubular dysfunction and n eurological deficits, The gene responsible for this disorder, OCRL-1, has been cloned and mutations identified in patients. The gene product (ocrl-1) has extensive sequence homology to a 75 kDa inositol polypho sphate 5-phosphatase. We report here that OCRL patients' fibroblasts s how no abnormality in inositol polyphosphate 5-phosphatase activity, b ut are deficient in a phosphatidylinositol 4,5-bisphosphate [PtdIns(4, 5)P-2] 5-phosphatase activity localized to the Golgi apparatus, Direct biochemical diagnosis of this human disease should now be possible. P tdIns(4,5)P-2 has been implicated in Golgi vesicular transport through its role in the regulation of ADP-ribosylation factor, phospholipase D and actin assembly in the cytoskeleton, The regulation of PtdIns(4,5 )P-2 levels by PtdIns(4,5)P-2 5-phosphatase may, therefore, be importa nt in the modulation of Golgi vesicular transport, Given that the prim ary defect in OCRL is a deficiency of a Golgi PtdIns(4,5)P-2 phosphata se, we hypothesize that the disorder results from dysregulation of Gol gi function and in this way causes developmental defects in the lens a nd abnormal renal and neurological function.