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Scientists Report on Sheila Essey Award-Winning C9orf72 Gene Research

April 16, 2013

During the Sheila Essey Award for ALS Research presentation at the 2013 American Academy of Neurology annual conference in San Diego, Calif., two scientists discussed their finding on this ground-breaking research.

Rosa Rademakers, Ph.D., had to design a new test to find it. Bryan Traynor, M.D., Ph.D., went first to Finland and then to Wales to find it. They were both looking for the elusive gene on chromosome 9 that is now known to be the most common genetic cause of ALS. The two scientists discussed their independent discoveries after receiving the Sheila Essey Award from The ALS Association and the American Academy of Neurology. Dr. Rademakers is Associate Professor of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, Fla. Dr. Traynor is a neurologist and an Investigator at the National Institute on Aging (NIA), where he has been the Chief of the Neuromuscular Diseases Research Unit at the Laboratory of Neurogenetics since 2009.

Both Drs. Rademakers and Traynor knew there was an important ALS gene located on chromosome 9, which had been identified in previous studies of large numbers of ALS patients. But for years, it defied discovery despite the efforts of genetic researchers throughout the world. The region contained only a few genes, Dr. Rademakers explained, “but our genetic methods couldn’t find the mutation.” In hindsight, she said, it became clear that the structure of the gene mutation was the problem—it was too long and too repetitious to be identified by standard gene discovery tools.

Recognizing the limitations of those tools, Dr. Rademakers hypothesized that the mutation might be just the type of repeat that would be hard to find with them. So she designed a new assay that detected long, repetitive portions of DNA. When she analyzed the C9orf72 gene from ALS patients, the readout from the assay gave a “stutter pattern,” a series of peaks of ever-diminishing size when the gene was copied in the lab, indicating how repetitive the mutation is. “All the affected individuals in our ALS family had the stutter pattern and none of the 1000 controls did. It was very exciting to see,” she said.

Dr. Traynor explained that international collaborations were crucial in helping to find the gene. The chromosome 9 region became an especially sought-after target when a study of the Finnish population identified a major ALS gene there. He also studied a family from Wales, trekking to one village so small “you’d miss it if you blinked” in order to take samples from a family with ALS. He too was puzzled by the inability to find the mutation with the regular gene-hunting tools, and he also concluded it had to be a novel sort of mutation.

The mutation accounts for about one third of all familial ALS cases, and about 6% of sporadic (non-familial) cases. In addition, it is responsible for one quarter of all familial cases of frontotemporal dementia, a related neurodegenerative disease.

“We don’t yet know how the repeat causes the disease,” Dr. Rademakers said. There are several hypotheses, with evidence supporting several different mechanisms. The function of the normal protein is unknown, but the reduced levels of it caused by the mutation may be harmful. The repeat on the DNA causes the formation of a long ribonucleic acid (RNA) strand, which may trap other cellular molecules with harmful consequences. And the long RNA strand may be read the wrong way by the cellular protein-making machinery, leading to unusual and potentially harmful proteins. Researchers are now exploring all these possibilities.

“There is still a long way to go,” Dr. Traynor said. But he noted that ALS researchers worldwide are working together on solving the riddle of the C9orf72 gene. “Gone are the days of the single scientist working on the causes of disease. Genetics and genomics is now a team sport.” That cooperation is poised to allow scientists to make major strides in understanding, and treating, this important cause of ALS. Those same efforts will help accelerate treatments for all forms of the disease.

In 1996, The ALS Association and the AAN inaugurated the Sheila Essey Award for ALS Research to acknowledge and honor individuals actively engaged in ALS research who is making significant contributions in research for the cause, treatment, prevention or cure for ALS. The award is made possible through the generosity of the Essey Family Fund, in memory of Sheila Essey, who battled ALS for ten years and died from the disease in 2004. Past recipients have used the funds to continue ALS research or to support promising young scientists on their research teams.

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