The gene, found on chromosome 12, normally contains a string of 15 to 29 repeats of a three-base (trinucleotide) sequence in the genetic code -- cytosine, adenine, and guanine, or CAG. In people with SCA2, however, the gene contains from 36 to 59 CAG repeats. Each CAG trinucleotide codes for a single amino acid called glutamine, so these CAG repeats result in a long string of glutamines (also known as a polyglutamine) that interrupts the sequence of a normal protein. CAG repeat mutations have previously been linked to Huntington’s and four other diseases.

The discovery of the SCA2 gene will allow more specific genetic testing for people with hereditary ataxias, says Stefan Pulst, MD, of Cedars-Sinai Medical Center at the University of California, Los Angeles. Pulst, a grantee of the National Institute of Neurological Disorders and Stroke (NINDS), is lead author on one report. Hereditary and sporadic ataxias combined affect an estimated 150,000 Americans. Scientists previously identified the genes for two other spinocerebellar ataxias (SCA 1 and 3), and recent genetic linkage studies suggest that there may be four more. The symptoms of these diseases often overlap, as do the ages of onset. One family with SCA2 might develop ataxia, for example, while another might show dementia and chorea (involuntary movements) resembling Huntington’s disease.

Before genetic testing became available, the only way to diagnose ataxias was by clinical histories. "It was like a bag of mixed beans," says Giovanna Spinella, MD, a pediatric neurologist from NINDS. "You had no way of knowing which beans were inside." With genetic testing, families can now learn with certainty which disease affects them and better predict the course and transmission of the disease. Since SCA2 mutations are dominant, only one parent needs to pass on a mutated gene for the disease to appear in his or her offspring.

The six diseases linked to CAG repeat mutations include SCA2; Huntington’s disease; spinocerebellar ataxia 1 (SCA1); dentatorubral-pallidoluysian atrophy (DRPLA); spinocerebellar ataxia 3 (SCA3 or Machado-Joseph disease); and spinobulbar muscular atrophy (Kennedy’s disease). Three other diseases, fragile X syndrome, myotonic muscular dystrophy, and Friedreich’s ataxia, are linked to different kinds of trinucleotide expansions.

The new gene discovery provides important clues about how CAG trinucleotide repeats may cause disease. All diseases in the CAG repeat family show genetic anticipation, meaning the disease usually appears at an earlier age and increases in severity with each generation. Genetic anticipation is linked to increasing numbers of CAG repeats, which result from expansion of the unstable CAG sequence when reproductive cells divide to form eggs and sperm.

In SCA2, the most common disease-causing sequences contain only 37 CAG repeats, fewer than the number found in genes from many people without disease. While the number of repeats is important, therefore, other factors such as the polyglutamine segment’s interaction with nearby proteins probably determine whether or not disease develops. Learning how polyglutamines cause different diseases may lead to new strategies for treating these diseases. Because the brain cells that die in SCA2 also die in other neurodegenerative diseases, these studies could potentially help researchers understand Alzheimer’s, Parkinson’s, and similar disorders.

Results from the three studies show that two forms of the SCA2 gene (containing 22 and 23 CAG repeats) predominate in the normal population. This contrasts with the other CAG repeat disease genes, which occur in many forms among normal individuals. The relative stability of the normal SCA2 genes probably results from inclusions of CAA (cytosine, adenine, adenine) trinucleotides in the CAG chains. These CAA sequences code for glutamine just as CAG does, but they change the structure of the CAG chain so that it is less likely to expand, says Pulst.

The SCA2 gene product, ataxin-2, is unlike any previously identified protein. However, the gene is active in many body tissues, including the brain, heart, liver, pancreas, skeletal muscle, and placenta. One part of ataxin-2 resembles a segment from non-polyglutamine protein (ataxin-2 related protein or A2RP) that is identical in humans and mice. The SCA2 gene in mice also lacks CAG repeats. This suggests that the polyglutamine in ataxin-2 is unnecessary, a bystander that does not affect the protein’s function unless it expands.

The exact number of people affected by SCA2 is unknown, but Pulst estimates that the number could be as high as one or two in every 100,000 people. It appears to be about twice as common as SCA1, he says. Now that the SCA2 gene has been found, researchers can more accurately determine how many people are affected by the disease.

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.

(This release will be available on the World Wide Web at http://www.nih.gov/ninds/)