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New Type of Trinucleotide Mutation Found in Friedreich's Ataxia


For release: Thursday, March 7, 1996

Scientists have identified a new type of trinucleotide repeat mutation that leads to Friedreich's ataxia (FA), a rare childhood neurodegenerative disease. The discovery allows accurate screening for carriers of the disease and may lead to the first effective treatments.

The mutation contains between 200 and 900 repeats of a normal three-base (trinucleotide) sequence -- guanine, adenine, and adenine, or GAA -- in a newly described gene called X25. The normal gene contains only seven to 22 repeats. Mutated X25 genes produce much less messenger RNA, an intermediate step in protein production, than normal genes.

X25 normally codes for a protein called frataxin that is concentrated in the organs affected by FA, says Dr. Massimo Pandolfo of Baylor College of Medicine in Houston. Frataxin is unlike any previously described protein, and scientists are just beginning to learn how it works. Pandolfo conducted the study in collaboration with scientists from France, Spain, and Italy. The work was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and by the Muscular Dystrophy Association. It appears in the March 8, 1996, issue of Science.*

About 98 percent of FA carriers have the expanded GAA sequence, so scientists can now diagnose carriers very accurately, Pandolfo says. Studying how X25 and frataxin function also will help researchers understand the disease and design treatments for it, he says.

FA affects several thousand people in the United States and causes degeneration of the spinal cord and its brain connections, the heart, and the pancreas. Symptoms typically appear between the ages of five and 25 and include progressive loss of coordination (ataxia), lack of leg tendon reflexes, and speech slurring. Most patients also develop heart enlargement, and about 10 percent acquire diabetes mellitus. At present there is no treatment to slow progression of the disease, and patients eventually must rely on a wheelchair. They also have a shortened life expectancy, averaging 37 years.

Unlike mutations in other trinucleotide expansion diseases, including Huntington's disease, the FA mutation is genetically recessive. This means a child must inherit two mutated copies of the gene -- one from each parent -- to develop the disorder. Preliminary results suggest that, in contrast to other trinucleotide expansions, the number of repeats in the FA mutation does not correlate with disease severity or age of onset. People carrying only one altered copy of the gene do not have FA but can pass the mutation to their children. Previously described trinucleotide repeat mutations are dominant, meaning only one altered copy of the gene leads to disease.

Since carriers of FA are themselves unaffected by the mutation, they are usually unaware of it and tend to have the same number of children as other people. This accounts for the relatively high frequency of carriers in the population -- about one in 100 people, according to the National Ataxia Foundation.

The FA trinucleotide expansion is the first disease-causing mutation found to occur in an intron. Introns code for sequences that are cut out of messenger RNA before proteins are assembled. Scientists have long wondered what function introns serve. The FA mutation supports previous evidence that they influence gene expression.

Along with the trinucleotide expansion, Pandolfo and his colleagues identified three single-nucleotide "point" mutations that inactivate the X25 gene and lead to disease. These mutations affected only eight of the 184 FA patients examined. These patients all had the expanded GAA repeat on the X25 gene from their other parent. "Patients with FA either have both genes with the unstable expansion, or they have one gene with the unstable expansion and the other with a point mutation," says Dr. Giovanna Spinella, a pediatric neurologist at NINDS.

While frataxin's function is still unclear, it includes a 27 amino acid sequence that is nearly identical to sequences from a worm species (C. elegans) and yeast (S. cerevisiae), Pandolfo says. The similarity of this sequence in such diverse species, which are separated by millions of years of evolution, suggests that it plays a critical role in organisms' survival. The rare "point" mutations all affect this region of the protein, underscoring its importance.

Studying how frataxin works in other species may help scientists learn what it does in humans and design treatments for FA, Pandolfo says. He and his colleagues are now working to further define frataxin's function. This work may reveal new protein interactions that are important to all cells, not just those affected by FA.

FA is the eighth disease linked to trinucleotide repeat mutations. The others are Huntington's disease, spinocerebellar ataxia type 1 (SCA1), X-linked spinobulbar muscular atrophy (Kennedy's disease), dentatorubral and pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 3 (SCA3 or Machado-Joseph disease), fragile X syndrome, and myotonic dystrophy. FA is the first disease linked to an expanded GAA sequence.

The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain.

*Campuzano, V.; Montermini, L.; Molto, M.D.; Pianese, L.; Cossee, M.; Cavalcanti, F.; Monros, E.; Rodius, F.; Duclos, F.; Monticelli, A.; Zara, F.; Canizares, J.; Koutnikova, H.; Bidichandani, S.; Gellera, C.; Brice, A.; Trouillas, P.; De Michele, G.; Filla, A.; De Frutos, R.; Palau, F.; Patel, P.I.; Di Donato, S.; Mandel, J.-L.; Cocozza, S.; Koenig, M.; Pandolfo, M. "Friedreich Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion." Science, Vol. 271, March 8, 1996 (pp.1423-1426).

Originally prepared by Natalie Larsen, NINDS Office of Communications and Public Liaison.

Last Modified August 7, 2009