Taking The 'Mute' Off Silenced Gene May Be Answer To Angelman Syndrome

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Most genes are inherited as two working copies, one from the mother and one from the father. However, in a few instances, a gene is imprinted, which means that one copy is silenced. This is called genomic imprinting. If the active copy is mutated, then disease results, even though the silenced gene copy may be normal.

Angelman syndrome, which causes learning difficulties, speech problems, seizures, jerky movements and an unusually happy disposition, results when a gene inherited from the mother in a particular area of chromosome 15 is mutated and the other copy of the gene, inherited from the father, is silenced. In a report that appears online in the journal Nature¸ researchers answer the question: "Can we turn on the activity of the paternal gene?"

Angelman syndrome occurs when an infant inherits a mutated copy of the imprinted gene UBE3A from his or her mother. He or she also has a paternal copy of the gene, but it is silenced by a long ribbon of RNA called the UBE3A anti-sense transcript. (Antisense, in this case, is complementary to the ribbon of RNA, which means it binds to it and silences any activity.)

In an earlier experiment, researchers showed that a type of drug called a topoisomerase could activate the father's copy of the gene, but the drug itself was toxic and it did not limit activation to the Angelman gene but affected all long genes.

In the current study, researchers bred a mouse in which the antisense transcript was "knocked down" and the paternal copy of the gene turned on. The treatment worked both in cells in the laboratory and in the live animals. The effect of the injection of the antisense oligonucleotides used lasted about 16 weeks.
 
The researchers anticipate that if the laboratory and animal studies continue to be positive, a study in children with the problem could be possible in the next two to three years. Perhaps, they said, the technique could be modified to work in other diseases that result from mutations in imprinted genes.