The isolation, cloning and mapping of the human gene for aphosphate-cleaving enzyme involved in intracellular signaltransmission by researchers at Washington University School ofMedicine may have led investigators one tiny step closer toidentifying the gene for manic depression.
The link, tenuous as it is, has to do with lithium, the drug ofchoice for treating manic depression. It turns out that inositolpolyphosphate 1-phosphatase -- the particular enzymereported on by Philip Majerus and his associates in Tuesday'sissue of the Proceedings of the National Academy of Sciences --is uncompetitively inhibited by lithium.
Moreover, the levels of lithium needed to inhibit the enzymeare the same as those achieved intracellularly in psychiatricpatients being treated with lithium. Thus, although "it's a reachto claim that this (enzyme) is a cause of psychiatric disorders,it's worth exploring," Majerus told BioWorld.
The enzyme, inositol polyphosphate 1-phosphatase, is part ofthe phosphatidylinositol signaling pathway, which has beenshown to play a key role in the way cells respond to externalstimuli.
Majerus and his colleagues plucked out the human gene for theenzyme by hybridizing it with a complementary DNA encodinga bovine version, with which it shares 84 percent amino acidsequence identity.
The researchers also detected the gene's messenger RNA in anumber of human tissues, most notably the pancreas andkidney, and confirmed that the human enzyme functioned byexpressing it in heterologous systems, including fibroblasts andEscherichia coli. Moreover, they localized the inositolpolyphosphate 1-phosphatase gene to chromosome 2 byfluorescence in situ hybridization.
That Majerus and his associates have actually placed the geneon a chromosome may provide a starting point for linkageanalysis to tie it to defects that manifest as mental disorders."There have been a number of false starts over the years tolink manic depression to different chromosomes," Majerus toldBioWorld, "but there's been no work done on chromosome 2."
-- Jennifer Van Brunt Senior Editor
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