The ALS Association

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ALS Researchers Discover Unprecedented Details of Gene Mutation’s Effects

March 5, 2014

In work supported by The ALS Association and published in the science journal Nature, researchers have discovered significant new details of the pathological effects of the most common ALS gene, C9orf72.

Association-supported researcher Jiou Wang, Ph.D., of Johns Hopkins University in Baltimore, Md., led the study. Dr. Wang and his colleagues focused on mutations in the gene, which account for up to 40 percent of familial ALS and 6 percent of sporadic ALS. The mutation is an expansion of a six-nucleotide GGGGCC section of the gene (a hexanucleotide repeat expansion, or HRE). The normal gene contains as few as two of these GGGGCC units, and the mutated gene may contain hundreds to thousands. Nucleotides function as the building blocks for both DNA, which makes up genes, and RNA, which carries genetic messages used to make proteins.

The researchers discovered that the expanded section of the gene folded into unusual looped structures, like spaghetti sticking to itself. These structures - called G-quadruplexes - formed in both the expanded DNA of the gene and the expanded RNA. The structures reduced the amount of protein that could be made from the gene and trapped multiple cell proteins that are involved in controlling gene expression. Cells from people with ALS due to the C9ORF72 gene displayed changes under the microscope, suggesting these structures caused stress in the cell nucleus, potentially contributing to disease.

“This important study gives us an unprecedented look at the effects of the C9ORF72 mutation,” said Lucie Bruijn, Ph.D., MBA, Chief Scientist for The Association. “It is now imperative that we follow up these observations with further work to clarify how these changes affect disease onset or progression. These insights will be critical in designing therapies to interrupt these processes.”

This study was funded by Mrs. Corinne Schwartz and Family.

Read the press release.

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