Researchers discover Lowe syndrome gene causes enzyme deficiency
Diagnostic test available soon
In a stunning year-end announcement, researchers reported that they have discovered the basic metabolic defect in Lowe syndrome. In a paper published in the December 1995 issue of Human Molecular Genetics, Robert L. Nussbaum, M.D., and his colleagues at the National Institutes of Health in Bethesda, Maryland, reported their discovery that the defective Lowe syndrome gene causes the deficiency of an enzyme that is essential to inositol metabolism.
The team's research indicated that cell lines from fibroblasts (skin samples) of individuals with Lowe syndrome are missing an enzyme called phosphatidylinositol 4,5-biphosphate 5 phosphatase. This enzyme removes one molecule of phosphate from a phospholipid called phosphatidylinositol 4,5-biphosphate (or PtdIns[4,5]P2 for short) and converts it into phosphatidylinositol 4-phosphate (PtdIns[4]P for short).
In a separate paper, the researchers announced the additional discovery that this enzyme is essential to normal metabolic processes that take place in a certain part of the cell called the Golgi apparatus. Because of the PtdIns(4,5)P2 deficiency, the cell functions that are regulated by the Golgi are abnormal, leading to the developmental defects in Lowe syndrome, including cataracts and kidney and brain problems.
The finding of the basic defect in Lowe syndrome means a biochemical test for diagnosis will be available for the first time. Families will no longer have to go through months (or even years in some cases) of uncertainty and endless tests in order to obtain a diagnosis. An accurate diagnosis can now be made by having a small skin sample analyzed for the presence or absence of the PtdIns(4,5)P2 5-phosphatase enzyme.
Preparations are underway to set up clinical testing in two laboratories, one at Baylor College of Medicine in Houston and the other at Johns Hopkins in Baltimore. Families will not have to travel to a lab to have the test performed, however. Samples can be taken in the local community and arrangements for sending samples for testing can be made by local physicians. Further details for arranging testing will be announced in future issues of On the Beam. The cost for the test is not yet known. Individual families will need to contact their insurance carrier to check on coverage.
In addition to the new diagnostic test, the discovery of the enzyme deficiency may lead to a prenatal test. Researchers are currently evaluating this possibility. The discovery will probably not lead to a carrier test, however, because enzyme levels in carriers is likely to be too variable, according to Nussbaum.
Calling the discovery "breathtaking," LSA Medical Research Chair Kaye McSpadden said it is "the most significant research breakthrough since the gene itself was found in 1992. Not only do we now know what's wrong in Lowe syndrome, but researchers have given us real help for real people. We should be able to prevent inaccurate diagnoses as well as finally answer the question 'does he or doesn't he?' in a number of cases."
Despite the landmark discovery of the enzyme deficiency, much more work remains to be done in order to fully understand all the metabolic processes involved in Lowe syndrome and to develop effective treatments. For instance, the defect cannot be "fixed" simply by replacing the missing enzyme with oral supplements, for several reasons. First, it is not known why a defect in this enzyme causes Lowe syndrome. Is it because of a failure to break down PtdIns(4,5)P2 or does it result from a deficiency of the substance that PtdIns(4,5)P2 is converted to, phosphatidylinositol 4-phosphate (PtdIns[4]P)?
Second, the enzyme appears to be located in a small subcompartment of the cell, the Golgi apparatus. There is currently no method available to target the enzyme to this particular location, to remove increased PtdIns(4,5)P2 or to replace decreased PtdIns(4)P through oral supplements.
Third, the biochemical defect appears to be a subtle imbalance in PtdIns(4,5)P2 in the Golgi and, therefore, methods to correct the defect are likely to require equally subtle correction. In other words, overcorrection could be just as harmful as the original lack of the enzyme.
With further investigations, researchers may be able to identify the metabolic steps that are disrupted by the lack of PtdIns(4,5)P2 and try to find ways to deliver the enzyme to the proper place in the cell (by gene therapy) or find other ways to compensate for the deficiency. However, given the subtle nature of the chemical defect, its localization in only a small part of the cell, and the difficulties involved with treating diseases that begin prior to birth by gene therapy, therapeutic methods are, a long way off.
Nevertheless, families and friends of individuals affected by Lowe syndrome recognize the significance of this discovery and gratefully and enthusiastically say "thank you" to Dr. Nussbaum and his team of six researchers who have been working full-time on the Lowe syndrome project. LSA members can be heartened not only by the hope and help of
this monumental discovery, but by the knowledge that the research continues. LSA members will have the opportunity to learn more about the discovery and the continuing research from Dr. Nussbaum himself at the LSA conference in California in June.
In the meantime, the LSA will continue its efforts to keep the membership informed of new developments. Ironically, the recently published revised edition of Living with Lowe Syndrome is now out of date. According to McSpadden, an addendum with the new information will be prepared during the next few months and inserted in the booklet. In addition, the LSA has announced its 1996 Medical Research Grant in the amount of $12,000, to encourage and support further research.
For readers who are interested in obtaining copies of the scientific papers reporting these discoveries, the citations follow. Copies can also be provided upon request by the LSA.
Olivos-Glander IM, Janne PA, Nussbaum RL (1995): The oculocerebrorenal syndrome gene product is a 105-kD protein localized to the Golgi complex. American Journal of Human Genetics 57:817-823.
Suchy SF, Olivos-Glander IM, and Nussbaum R.L. (1995): Lowe syndrome, a deficiency of a phosphatidylinositol 4,5 bisphosphate 5-phosphatase in the Golgi apparatus. Human Molecular Genetics 4:2245-2250.
OTB, Winter/Spring, 1996, v.15:1
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