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Scientists uncover new genetic mutation for ALS and FTD

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An international team of scientists has identified a novel genetic mutation for amyotrophic lateral sclerosis (ALS) and a related disease called frontotemporal dementia (FTD), which experts say represents over 33% of all inherited cases of these diseases. . Published in the journal Neuron, the findings reveal that this mutation, in the C9ORF72 gene, is about twice as common as all other mutations found to date for the disease combined. Scientists can use the findings to create new animal models of ALS, and then novel targets to fight the more common sporadic form of the disease. ALS is not an inherited disease; it can emerge in anyone.

Researchers led by Johns Hopkins University School of Medicine in the United States say that despite the fact that a number of other genetic mutations have been associated with inherited or familial ALS and FTD, these mutations represent only 25% of cases. Because no information existed on other mutations that trigger ALS and FTD, the team decided to investigate the short arm of chromosome 9, an area that other studies had suggested might hold promise for uncovering the mystery of which genes could be affected.

'If you think of chromosomes like geographic regions, we knew what city this mutation was located in, and what part of the city, but we didn't know what street it was located on or which house,' says Professor Bryan J. Traynor from the Department of Neurology at Johns Hopkins, who is also the head of the Neuromuscular Diseases Research Unit at the National Institutes of Health (NIH) and the leader of this study. 'We were really looking for the exact address for this mutation.'

The team, consisting of experts from Canada, Finland, Germany, Italy, the Netherlands, the United Kingdom and the United States, narrowed down the location of the mutation by utilising a next-generation genomic sequencing technique on pieces of chromosome 9 sampled from ALS and FTD patients in unrelated Welsh and Dutch families that have been dealing with the diseases over the course of several generations. The researchers compared sequences from these infected individuals to a healthy group, which consisted of unaffected relatives and people outside these families who had never been diagnosed with ALS or FTD.

The data show that the sequences revealed an unusual section of chromosome 9 near the C9ORF72 gene in which a six-base DNA (deoxyribonucleic acid) sequence (GGGGCC) was repeated again and again.

Following their evaluation of DNA samples from other patients with familial ALS and FTD from Finland, which is the country with the highest incidence of these diseases on the planet, the researchers found that this unusual segment was present in around 50% of the cases.

'Together with another mutation in a previously discovered familial ALS gene known as SOD1,' says Professor Traynor, 'this means that we are now able to explain nearly all of familial ALS disease in Finland.'

To substantiate the data, the team tested samples from German, Italian and North American patients. Around 38% of patient samples had repeats; it should be noted though that the repeats were not present in healthy individuals.

Professor Traynor points out, however, that it is still unclear as to how the repeated segments could be responsible for ALS and FTD. While they may impact the function of C9ORF72, the researchers believe a more likely mechanism is that the repeated segments kick-start the affected cells into producing a slew of toxic ribonucleic acid (RNA), genetic material that clogs up cells and triggers their demise.

Why ALS and FTD tend to emerge in middle age instead of younger years could be due to the slow build up of toxic RNA, according to the team. 'Eventually, the finding could help scientists find new ways to treat both familial ALS and FTD, as well as the more common sporadic forms of these diseases,' Professor Traynor concludes