Unusual genetic mutation linked to disabling brain disease

Published: July 19th, 2010

Category: MBI Announcements

Researchers have discovered a genetic mutation that contributes to a rare brain disease that causes patients to lose control of their coordination and movements.

Writing in PLoS Genetics, scientists with the University of Florida’s McKnight Brain Institute and the University of Texas Medical Branch describe how an elongation of a segment of RNA — the molecule that executes instructions within the cell — causes the death of vital brain cells in patients with spinocerebellar ataxia type 10 (SCA10).

Tetsuo Ashizawa, M.D., is the chairman and the Melvin Greer professor of the department of neurology.

Tetsuo Ashizawa, M.D., is the chairman and the Melvin Greer professor of the department of neurology.

Spinocerebellar ataxias (SCAs) are a group of more than two dozen genetic diseases that degenerate the cerebellum, the brain’s coordination center. Individuals with SCAs have impaired balance and coordination. Most SCAs are caused by gene mutations that change the amino acid sequence of the protein that the gene encodes.

Unlike other forms of ataxia, SCA10 has only been found in people of Mexican, Brazilian or Brazilian heritage with Amerindian admixture. It usually strikes patients in their middle 30s. Patients gradually become worse, to the point of total disability, and more than half of them suffer from seizures that can become life-threatening.

“These patients have a mutant gene that produces the toxic RNA with an elongated segment containing too many repeated component units,” said Tetsuo Ashizawa, M.D., chairman of neurology at the UF College of Medicine and the investigator who discovered the SCA10 mutation. “That segment of RNA produced from the normal gene is degraded and not used to produce the protein; however, when the RNA segment has too many repeats due to the mutated gene, it resists degradation, accumulates and triggers a cascade of events that lead to cell death.

“Knowing this may give us therapeutic insight toward developing a drug that can silence this toxic RNA,” Ashizawa said. “Each of the repeated unit consists of the chemical sequence of adenine-uracil-uracil-cytosine-uracil (AUUCU), which has not been found to be involved in any other human diseases. This discovery has a scientific and medical impact because the SCA10 is the first example of this type of mutation in human diseases, and understanding the disease mechanism of SCA10 can help advances in research on other SCAs and related neurodegenerative disorders.”