Lowe syndrome, a deficiency of phosphatidylinositol 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 neurological 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 polyphosphate 5-phosphatase. We report here that OCRL patients' fibroblasts show no abnormality in inositol polyphosphate 5-phosphatase activity, but are deficient in a phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] 5-phosphatase activity localized to the Golgi apparatus. Direct biochemical diagnosis of this human disease should now be possible. PtdIns(4,5)P2 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)P2 levels by PtdIns(4,5)P2 5-phosphatase may, therefore, be important in the modulation of Golgi vesicular transport. Given that the primary defect in OCRL is a deficiency of a Golgi PtdIns(4,5)P2 phosphatase, we hypothesize that the disorder results from dysregulation of Golgi function and in this way causes developmental defects in the lens and abnormal renal and neurological function.
Suchy
S F
SF
Laboratory of Genetic Disease Research, National Center for Human Genome Research, National Insititues of Health, Bethesda, Maryland 20892, USA.
Olivos-Glander
I M
IM
Nussabaum
R L
RL
D002460:Cell Line; D003001:Cloning, Molecular; D006056:Golgi Apparatus / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D009800:Oculocerebrorenal Syndrome / Q000201:enzymology* / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D000099182:Phosphoinositide 5-Phosphatases
D010744:Phosphoric Monoester Hydrolases; D011506:Proteins; D000099182:Phosphoinositide 5-Phosphatases; C075695:OCRL protein, human