Lowe syndrome

Monnet et al. (M12) report that among 15 children below one year of age, suffering from congenital glaucoma, one developed a typical Lowe syndrome and four others presented hyperamino aciduria as the only extra pathological feature. In three other cases of this disease (two brothers and one third cousin), one of which reached adult age, there was a definite hyperamino aciduria, namely, a large excretion of glutamic acid by the two brothers (G4). 

In part two, we review the role of Pis in human disease. Although Pis are not abundant in biological systems, they have displayed numerous important functions in multiple signal transduction pathways. A number of human diseases are characterized by dysfunctional PI pathways, including cancer, type 2 diabetes, Lowe syndrome, myotubular myopathy, and Charcot-Marie-Tooth disease. 

Abnormalities in the actin cytoskeleton, including decreased actin stress fibers and altered response to depolymerizing agents were also observed in Lowe patients (Suchy and Nussbaum, 2002). Two actin-binding proteins, gel-solin and alpha-actinin, which are regulated by both PIP2 and Ca2+ were found to be abnormally distributed. Actin polymerization plays a key role in cell -cell contacts, which may be defective in Lowe syndrome. 

Janne, P.A., Suchy, S.F., Bernard, D., MacDonald, M., Crawley, J., Grinberg, A., Wynshaw-Boris, A., Westphal, H., and Nussbaum, R.L., 1998, Functional overlap between murine Inpp5b and Ocrll may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. J. Clin. Invest. 101 2042-2053. 

Monnier, N., Satre, V, Lerouge, E., Berthoin, F., and Lunardi, J., 2000, OCRL1 mutation analysis in French Lowe syndrome patients Implications for molecular diagnosis strategy and genetic counseling. Hum. Mutat. 16 157-165. 

Suchy, S.F., and Nussbaum, R.L., 2002, The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization. Am. J. Hum. Genet. 71 1420-1427. 

Suchy, S.F., Olivos-Glander, I.M., and Nussabaum, R.L., 1995, Lowe syndrome, a deficiency of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi apparatus. Hum. Mol. Genet. 4 2245-2250. 

Ungewickell, A.J., and Majerus, P.W., 1999, Increased levels of plasma lysosomal enzymes in patients with Lowe syndrome. Proc. Natl. Acad. Sci. U. S. A. 96 13342-13344. 

Zhang, X., Hartz, P.A., Philip, E., Racusen, L.C., and Majerus, P.W., 1998, Cell lines from kidney proximal tubules of a patient with Lowe syndrome lack OCRL inositol polyphosphate 5-phosphatase and accumulate phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 273 1574-1582. 

Mutations that cause Lowe syndrome have been mapped exclusively to the OCRLl gene. The overwhelming majority of missense mutations are localized to the... 

Surprisingly, OCRLl knock-out mice do not develop Lowe syndrome. A potential explanation for this observation is that the OCRLl loss of function is compensated by the phosphatase, InppSb, which shares high homology with OCRLl, and which is more expressed in mice than in humans (Jefferson and Majerus, 1995 Janne et al., 1998 Hellsten et al 2001 Astle et al., 2006). 

Hyvola N, Diao A, McKenzie E, Skippen A, Cockcroft S, Lowe M (2006) Membrane targeting and activation of the Lowe syndrome protein OCRLl by tab GTPases. EMBO J 25 3750-3761 Mow JK, Restifo LL (2004) Molecular and comparative genetics of mental retardation. Genetics 166 835-881... 

Lowe M (2005) Structure and function of the Lowe syndrome protein OCRLl. Traffic 6 711-719... 

Zhang X, Jefferson AB, Auethavekiat V, Majerus PW (1995) The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase. Proc Nad Acad Sci USA 92 4853-4856... 

Pelizaeus-Merzbacher disease p Alport-like hereditary nephritis [pabry disease q Lowe syndrome Immunodeficiency, X-linked r with hyper IgM Lymphoproliterative syndrome s Hemophilia B t Albinism-deafness syndrome u Fragile X syndrome Hunter syndrome Hemophilia A... 

Pelizaeus-Merzbacher disease p Alport-like hereditary nephritis Fabry disease q Lowe syndrome... 

PtdIns(4,5)P2 PH PLC5, PLD, dynamin Lowe syndrome, bacterial... 

Artefacts of MPS electrophoresis may be the same as for the DMB test, i.e. adhesives of urine collection bags. There is a large group of disorders -mostly affecting connective tissue metabolism - that have been associated with increased MPS excretion. Amongst these are the Lowe syndrome, osteopetrosis, rheumatoid arthritis, pycnodysostosis. 

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