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What happens when genetic information is not correctly edited in brain cells

Max Planck Society : 06 July, 2000  (Technical Article)
A correlation between impaired editing of RNA and epilepsy is reported by scientists from the Max Planck Institute for Medical Research in Heidelberg/Germany. They succeeded in correcting the defect by genetic manipulation in the mouse.
The soon-to-be-completed human genome sequence will ring in a new era for biomedical research. For the first time the primary structure of all genes which determine human form and nature will be known. The sequences of the four nucleotides in all genes allow us to predict from the genetic code the exact amino acid sequence of all human proteins. That, however, there will be exceptions where an exact prediction will not be possible, is the message of a scientific study from the Max-Planck Institute for Medical Research in Heidelberg which appears in the latest issue of Nature. The reason for the uncertainty in predicting correctly all human proteins is that some gene sequences undergo in certain cells an editing process during their expression as RNA templates for protein synthesis.

Editing of RNA is a rare process that has been observed in mammals only in few cell types. Editing of RNA means that one or a few nucleotides in the RNA become altered. This alteration of nucleotides in RNA leads to proteins that contain in one or a few positions a different amino acid than the one predicted from the gene sequence. The substitution of single amino acids in certain positions of the protein changes the protein's function. It is thought that editing allows for tuning a given protein's function to different physiological requirements.

Interestingly, in mammals, all genes whose RNA transcripts undergo editing play a role in brain function. These include in particular receptors for the neurotransmitter glutamate which are intimately involved in learning and memory acquisition.

The scientists from the department of Molecular Neurobiology at the Max Planck Institute for Medical Research focussed their studies on ADAR2, an editing enzyme, that is found in brain and many peripheral tissues. They succeeded to impair ADAR2-mediated editing by genetic manipulation in the mouse. Now, the proteins were composed as specified exactly by the nucleotide sequence on the gene. The Heidelberg team show in the Nature study that mice making unedited gene transcripts become prone to seizures when still quite young and that they die shortly after.

The scientists then introduced a point change (mutation) into the gene for the AMPA type of glutamate receptors, a key molecule for fast communication between nerve cells. They changed the gene such that it now had the sequence for the edited version and hence, this key protein for communication between nerve cells was again produced in a correct fashion in spite of the genetically induced impairment in RNA editing. To everyone's surprise, the phenotype of the mice normalized with the mice being seizure-free and exhibiting a normal life span. These experiments show clearly that this key protein in the brain is the main target for the editing events mediated by ADAR2.

Dr. Myoko Higuchi, who has worked in Germany for 20 years and who is the first author of the Nature publication, explained that the molecular components of the editing machinery are largely unknown. Moreover, the number of genes affected by editing is also unknown. When asked if human epileptic disorders might be evoked by defects in editing she replied that while this may seem possible, it has not been properly investigated.
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