New Gene Mutation Discovery by ALS Association Consortium is Major Research Breakthrough

 

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“This is a momentous discovery in furthering our understanding of ALS,” said Lucie Bruijn, Ph.D., senior vice president of research and development for The ALS Association. “A new gene provides a new piece of the puzzle we can use to shed light on why ALS develops, and where to focus our efforts on creating new treatments and finding a cure.”

The results of this groundbreaking research were published in the Friday, February 27 issue of the prestigious journal Science. The project was led by Tom Kwiatkowski M.D., Ph.D., at Massachusetts General Hospital, and Robert Brown, M.D., of the University of Massachusetts School of Medicine, and ALS Association-funded researchers Caroline Vance, Ph.D., and Christopher Shaw, M.D., of Kings College in London. The project was supported by a consortium of leading ALS researchers from around the world, formed as part of The Association’s Gene Identification Project. Their success reflects an unprecedented effort to accelerate the search for genetic mutations linked to all forms of ALS.

Dr. Brown noted, “We are particularly delighted because our trans-Atlantic consortium has pursued the chromosome 16 gene for more than six years. The ALS Association has been an all-important partner in this search. This discovery should lead to new cell and animal models of ALS, which will accelerate drug development.” 

“Global partnerships between investigators and funding agencies, such as the Motor Neuron Disease Association in the United Kingdom, are crucial to making these kinds of breakthroughs,” Dr. Bruijn commented. “This finding has opened up a whole new avenue of research and has the potential to uncover a common mechanism for most forms of ALS.”

The gene mutations were first identified by Dr. Kwiatkowski and were immediately confirmed by Dr. Vance, who also demonstrated abnormal accumulations of the mutant protein in cells cultured in the laboratory and the motor neurons of people carrying FUS mutations.

The gene, called FUS (“fused in sarcoma”), normally carries out multiple functions within motor neurons. These include regulating how gene messages (called messenger RNAs) are created, modified, and transported in order to build proteins. Some of these same functions also are performed by another gene called TARDPB encoding the protein TDP43, and mutations in the TDP-43 gene were recently linked to ALS as well.

“The fact that these two genes help perform the same function suggests that problems in this function may be critical in the development of ALS,” Dr. Bruijn said. “More research into exactly how these two genes work could ultimately lead to new treatments that are effective in slowing or stopping the progression of ALS and extending the lives of people with the disease.”

The mutations in the ALS6 gene were identified by detailed genetic sequencing in several families with an inherited form of ALS (familial ALS). Normally, the ALS6 protein works in the cell’s nucleus, but the mutations caused it to instead cluster outside the nucleus. Further work will be needed to determine precisely how this leads to ALS. With the gene in hand, scientists will be able to create cell and animal models containing the mutated gene, to examine in detail how the mutation operates and how it causes ALS.

“This suggests there may be a common mechanism underlying motor neuron degeneration,” according to Dr. Shaw. Motor neurons are nerve cells in the brain and spinal cord that control muscles. Motor neurons degenerate in ALS.

This is the second ALS-causing gene to be discovered in the past 12 months. SOD1, discovered in 1993, accounts for 20 percent of inherited cases of the disease. Mutations in the TARDP gene account for another four to five percent. The only well-defined causes of ALS are genetic. In both inherited and sporadic ALS, the disease symptoms and pathology are the same.

The possibility that ALS may be caused by several factors is the rationale for The Association’s policy of funding multiple genetic projects around the world and encouraging these leading geneticists to work together and share information to help locate disease-linked genes for faster, more accurate scientific results. By funding research on a global level, The Association helps put together “genetic pieces” of the ALS puzzle.

“Through our support of research such as this study, The ALS Association is committed to finding the causes of ALS, and using that knowledge to develop a cure as rapidly as possible,” Dr. Bruijn said. “We will build on the discovery of this new gene to carry that effort forward.”