Down syndrome: Supernumerary chromosome shut down

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Down syndrome: Supernumerary chromosome shut down

Researchers have for the first time normalized gene activity in trisomy 21

An international research team is a real breakthrough: the first time you have the extra chromosome turned in a down-patient cells - and thus corrected the cause of this genetic error. Yet the whole thing was indeed held only in a culture dish. The scientists however see this as an important first step towards a future gene therapy - and a way to learn more about the genetic roots of the disease, as the report in the journal "Nature".

Down syndrome: Supernumerary chromosome shut down

In Down syndrome, the chromosome 21 is three times before held twice

© National Human Genome Research Institute

"Down syndrome is the most common cause of mental retardation worldwide," explained Jeanne Lawrence of the University of Massachusetts Medical School in Worcester and colleagues. In Germany, about one in 500 children is born with this genetic defect, the risk increases with age of the mother. The cause is a surplus chromosome: Instead of normal two copies of the 21st chromosome wear down a third additional patients in their cells. Therefore, the syndrome is also referred to as Trisomy 21.

The physical and mental anomalies arise because during the development of the child, but also later, certain genes are present in the majority and are thus advised and disturbed the normal processes of balance. Until now, this genetic defect neither compensated nor be undone. "The correction of gene activity on a full excess chromosome was far far beyond our possibilities," says Lawrence.

Borrowed off of the female X chromosome

But there is in nature a mechanism that already does exactly this for millions of years: Every woman wears a pair of 23 two X chromosomes in their cells - and one of them is switched off. For a special RNA molecule called XIST which attaches to this chromosome and blocked the reading of all other genes makes. Lawrence and her colleagues wondered now: What if the XIST molecule other chromosomes can paralyze - and especially the surplus in Down's patients?

To investigate this, the researchers tested initially, whether the relatively large gene for the XIST molecule can ever inject into the genetic material of a cell. Indeed, this was achieved using a special enzyme. For the next step, the scientists a male Down-patient withdrawals, a cell sample and generated from induced stem cells - cells that can develop into very different tissue types. As in the original cells also wore these each a supernumerary chromosome 21.

In these cells, the researchers infiltrated the XIST a gene and activated it by a chemical substance. The results showed that 98.5 percent of the total of 245 cell colonies had installed the XIST gene in one of the three 21 chromosomes. The exciting moment but came after five days. Because then it was found that the produced from XIST gene RNA also appeared just as the female X chromosome.

Gene activity again as normal

In fact, the researchers found that the excess chromosome gradually changed: More and more appeared deposits the genetic material, which blocked the reading of genes. Simultaneously, the DNA began to contract and on, as Lawrence and her colleagues report.

Such an effect can also be observed in the now disused X chromosome: There is shrunk into a compact lump at cell edge, the so-called Barr body. Such Barr body was now. Also from the supernumerary chromosome 21 in the cells of patients with Down "With this method we have the excessive gene expression corrected in trisomy 21 to nearly normal dimensions", the researchers are observing. The treated cells showed the same gene activity as the control cells generated from a healthy donor.

First step to a chromosomal therapy

This breakthrough has the same meaning in three ways for research and medicine, says Lawrence. Firstly, it provides important information about how the silencing of chromosomes works. On the other hand can be combined with this method better than before explore which genes are responsible for which disabilities in trisomy 21 and how engaged their excessive activity in normal cell processes.

And finally, the third: "Our work opens up ways to chromosomes therapy for Down patients," says Lawrence. The successful experiment had shown that the first step in this direction, is the correction of the genetic defect in living cells, no longer insurmountable hurdle. Although it will take a long time before it can be developed and tested an applicable therapy. The researchers but see this as a real opportunity for the millions of sufferers worldwide.

doi: 10.1038 / nature12394

(University of Massachusetts Medical School, Worcester, 18.07.2013 - NPO)


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