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New Studies Identify the Most Common Genetic Cause of Familial ALS

International teams, including a Packard-funded investigator, show that a gene on chromosome 9 may explain 40% of all fALS cases.

Two papers published back-to-back today in Neuron by an international team of collaborators, including a Packard scientist, has uncovered a genetic mutation that may explain up to 50% of familial ALS cases in Finland and approximately 40% of familial ALS cases elsewhere in the US and Europe. Together with previously discovered genes, such as SOD1, TDP43, FUS and VCP, the new discovery means that the genetics of nearly two thirds of familial cases is now explained. The find, they say, is also important because it identifies a new mechanism by which a mutated gene can cause motor neuron disease.

The international collaborative study, led by Bryan Traynor, Chief of the Neuromuscular Diseases Research Unit at the National Institutes of Health and Packard Center scientist, identified a sequence of six nucleotides in a gene on chromosome 9 (known as C9ORF72) that can be repeated thousands of times in some patients with ALS. This hexanucleotide repeat is the most common genetic cause of ALS identified to date.

“This is a landmark paper in ALS research,” Traynor said. “It was unexpected how much of the genetics of ALS was explained by this mutation.”

The Finnish population was chosen for this study as it has the highest rate of ALS in the world. The newly identified hexanucleotide repeat, together with another known mutation in SOD1, means that nearly all familial ALS cases in this population are now explained.

These thousands of copies of the hexanucleotide repeat seen in many ALS patients may cause disease by creating toxic byproducts that alter RNA metabolism in the cell.

“Broadly speaking, these repeat expansions in non-coding regions cause disease in one of two ways. They can disrupt the gene that they’re in, causing the expression of that gene to go down. Or, when the gene is transcribed, the toxic RNA products from the repeat are transcribed along with it,” Traynor said. Preliminary evidence points to the latter hypothesis, he noted, and C9ORF72 is likely to cause disease by damaging the cells in the nerves and brain, where it is expressed and the toxic RNA accumulates.

Although researchers still don’t know exactly what C9ORF72 does in the cell, its identification is a huge breakthrough in ALS science.

“This is an exciting result. The finding takes us in a direction that we wouldn’t have otherwise thought to work on,” said Piera Pasinelli, the Science Director at the Packard Center for ALS Research, who was not involved in the study. “These results give us a new perspective on the types of genetic mutations seen in familial ALS patients and how to screen for them. They also put us to work right away to think of effective ways to build and study new disease models to understand how these mutations might lead to motor neuron death.”

Traynor received funding from the Robert Packard Center for ALS Research, The ALS Association’s Abendroth ALS Genetic Discovery Fund, and the National institute on Aging and the National Institute on Neurological Diseases and Stroke.

Traynor received funding from the Robert Packard Center for ALS Research, The ALS Association’s Abendroth ALS Genetic Discovery Fund, and the National Institute on Aging and the National Institute on Neurological Diseases and Stroke.

On the Web:

For More about Dr. Bryan Traynor: http://www.grc.nia.nih.gov/branches/lng/ndrg.htm
To read the papers published in Neuron: http://www.cell.com/neuron/abstract/S0896-6273(11)00797-5 and http://www.cell.com/neuron/abstract/S0896-6273(11)00828-2
To view the Packard Center press release: www.alscenter.org/news/_PDFs/Traynor Release 9.21.11.pdf
To view the Johns Hopkins press release: http://www.hopkinsmedicine.org/news/media/releases/new_genetic_mutation_for_als_identified

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